BIOLOGICALLY ACTIVE PEPTIDES FROM FUNCTIONAL DOMAINS OF BACTERICIDAL/PERMEABILITY-INCREASING PROTEIN AND USES THEREOF

Abstract: The present invention provides peptides having an amino acid sequnce that is the amino acid sequence of a human bactericidal/permeability-increasing protein (BPI) functional domain or a subsquence thereof, and variants of the sequence or subsequence thereof, having at least one of the BPI biological activities, such as heparin binding, heparin neutralization, LPS binding, LPS neutralization or bactericidal activity. The invention provides peptides and pharmaceutical compositions of such peptides for a variety of therapeutic uses.

Description: Biologically Active Peptides from Functional Domains of Bactericidal/ Permeability-Increasing Protein and Uses Thereof This is a continuation-in-part of U.S. Patent Application 08/183,222 filed January 14, 1994, which is a continuation-in-part of U.S. Patent Application 08/093,202, filed July 15, 1993, which is a continuation-in-part of U.S. Patent Application Serial No. 08/030,644 filed March 12, 1993. BACKGROUND OF THE INVENTION The present invention relates to peptides derived from or based on bactericidal/permeability-increasing protein and therapeutic uses of such peptides. Bactericidal/permeability-increasing protein (BPI) is a protein isolated from the granules of mammalian polymorphonuclear neutrophils (PMNs), which are blood cells essential in defending a mammal against invading microorganisms. Human BPI has been isolated from PMNs by acid extraction combined with either ion exchange chromatography (Elsbach, 1979, J. Biol. Chem. 254: 11000) or E. coli affinity chromatography (Weiss et al., 1987, Blood 69: 652), and has potent bactericidal activity against a broad spectrum of Gram-negative bacteria. The molecular weight of human BPI is approximately 55,000 daltons (55kD). The complete amino acid sequence of human BPI, as well as the nucleotide sequence of DNA encoding BPI, have been elucidated by Gray et al., 1989, J. Biol. Chem. 264: 9505, incorporated herein by reference (see Figure 1 in Gray et al.). The bactericidal effect of BPI has been shown to be highly specific to sensitive Gram-negative species. The precise mechanism by which BPI kills Gram-negative bacteria is not yet known, but it is known that BPI must first attach to the surface of susceptible Gram-negative bacteria. This initial binding of BPI to the bacteria involves electrostatic interactions between BPI, which is a basic (i.e., positively charged) protein, and negatively charged sites on lipopolysaccharides (LPS). LPS is also known as "endotoxin" because of the potent inflammatory response that it stimulates. LPS induces the release of mediators by host inflammatory cells which may ultimately result in irreversible endotoxic shock. BPI binds to Lipid A, the most toxic and most biologically active component of LPS. BPI is also capable of neutralizing the endotoxic properties of LPS to which it binds. Because of its Gram-negative bactericidal properties and its ability to bind to and neutralize LPS, BPI can be utilized for the treatment of mammals suffering from diseases caused by Gram-negative bacteria, including bacteremia, endotoxemia, and sepsis. These dual properties of BPI make BPI particularly useful and advantageous for such therapeutic administration. A proteolytic fragment corresponding to the amino-terminal portion of human BPI possesses the LPS binding and neutralizing activities and antibacterial activity of the naturally-derived 55kD human holoprotein. In contrast to the amino-terminal portion, the carboxyl-terminal region of isolated human BPI displays only slightly detectable antibacterial activity (Ooi et al., 1991, J. Exp. Med. 174: 649). One BPI amino-terminal fragment, comprising approximately the first 199 amino acid residues of the human BPI holoprotein and referred to as "rBPI^" (see Gazzano-Santoro et al., 1992, Infect. Immun. 60: 4754-4761) has been produced by recombinant means as a 23kD protein. rBPl 23 has been introduced into human clinical trials. Proinflammatory responses to endotoxin were significantly ameliorated when rBPI^ was co- administered with LPS. Other endotoxin binding and neutralizing peptides are known in the art. One example is Limulus antilipopolysaccharide factor (LALF) from horseshoe crab amebocytes (Warren et al. , 1992, Infect. Immunol. 60: 2506-2513). Another example is a cyclic, cationic lipopeptide from Bacillus polymyxa, termed Polymyxin B^ Polymyxin B_ is composed of six α,7-diaminobutyric acid residues, one D-phenylalanine, one leucine, one threonine and a 6- methyloctanoyl moiety (Morrison and Jacobs, 1976, Immunochem. 13: 813-818) and is also bactericidal. Polymyxin analogues lacking the fatty acid moiety are also known, which analogues retain LPS binding capacity but are without appreciable bactericidal activity (Danner et ah , 1989, Antimicrob. Agents Chemother. 33: 1428-1434). Similar properties have also been found with synthetic cyclized polymyxin analogues (Rustici et a , 1993, Science 259: 361- 365). Known antibacterial peptides include cecropins and magainins. The cecropins are a family of antibacterial peptides found in the hemolymph of lepidopteran insects (Wade et a , 1990, Proc. Nath Acad. Sci. USA 87: 4761- 4765), and the magainins are a family of antibacterial peptides found in Xenopus skin and gastric mucosa (Zasloff et a , 1988, Proc. Nath Acad. Sci. USA 85: 910-913). These peptides are linear and range from about 20 to about 40 amino acids in length. A less active mammalian cecropin has been reported from porcine intestinal mucosa, cecropin Pl (Boman et a , 1993, Infect. Immun. 6J.: 2978-2984). The cecropins are generally reported to be more potent than the magainins in bactericidal activity but appear to have less mammalian cell cytotoxicity. The cecropins and magainins are characterized by a continuous, amphipathic α-helical region which is necessary for bactericidal activity. The most potent of the cecropins identified to date is cecropin A. The sequence of the first ten amino acids of the cecropin A has some homology with the BPI amino acid sequence 90 - 99. However, the other 27 amino acids of cecropin A are clearly necessary for its bactericidal activity and there is little homology with BPI for those 27 amino acids. The magainins have even less homology with the BPI sequence. Of interest to the present application are the disclosures in PCT International Application PCT/US91/05758 relating to compositions comprising BPI and an anionic compound, which compositions are said to exhibit (1) no bactericidal activity and (2) endotoxin neutralizing activity. Anionic compounds are preferably a protein such as serum albumin but can also be a polysaccharide such as heparin. In addition, Weiss et ah (1975, J. Clin. Invest. 55: 33-42) disclose that heparin sulfate and LPS block expression of the permeability-increasing activity of BPI. However, neither reference discloses that BPI actually neutralizes the biologic activities of heparin. Heparin binding does not necessarily imply heparin neutralization. For example, a family of heparin binding growth factors (HBGF) requires heparin as a cofactor to elicit a biological response. Examples of HBGF's include: fibroblast growth factors (FGF-1, FGF-2) and endothelial cell growth factors (ECGF-1, ECGF-2). Antithrombin m inhibition of clotting cascade proteases is another example of a heparin binding protein that requires heparin for activity and clearly does not neutralize heparin. Heparin binding proteins that do neutralize heparin (e.g. , platelet factor IV, protamine, and thrombospondin) are generally inhibitory of the activities induced by heparin binding proteins that use heparin as a cofactor. BPI (including amino-terminal fragments thereof) has a number of other important biological activities. For example, BPI has been shown to have heparin binding and heparin neutralization activities in copending and co- assigned parent U.S. Patent Application Serial No. 08/030,644 filed March 12, 1993 and continuation-in-part U.S. Patent Application Serial No. 08/093,202, filed July 15, 1993, the disclosures of which are incorporated by reference herein. These heparin binding and neutralization activities of BPI are significant due to the importance of current clinical uses of heparin. Heparin is commonly administered in doses of up to 400 U/kg during surgical procedures such as cardiopulmonary bypass, cardiac catherization and hemodialysis procedures in order to prevent blood coagulation during such procedures. When heparin is administered for anticoagulant effects during surgery, it is an important aspect of post-surgical therapy that the effects of heparin are promptly neutralized so that normal coagulation function can be restored. Currently, protamine is used to neutralize heparin. Protamines are a class of simple, arginine-rich, strongly basic, low molecular weight proteins. Administered alone, protamines (usually in the form of protamine sulfate) have anti-coagulant effects. When administered in the presence of heparin, a stable complex is formed and the anticoagulant activity of both drugs is lost. However, significant hypotensive and anaphylactoid effects of protamine have limited its clinical utility. Thus, due to its heparin binding and neutralization activities, BPI has potential utility as a substitute for protamine in heparin neutralization in a clinical context without the deleterious side-effects which have limited the usefulness of the protamines. The additional antibacterial and anti-endotoxin effects of BPI would also be useful and advantageous in post- surgical heparin neutralization compared with protamine. Additionally, BPI is useful in inhibiting angiogenesis due in part to its heparin binding and neutralization activities. In adults, angiogenic growth factors are released as a result of vascular trauma (wound healing), immune stimuli (autoimmune disease), inflammatory mediators (prostaglandins) or from tumor cells. These factors induce proliferation of endothelial cells (which is necessary for angiogenesis) via a heparin-dependent receptor binding mechanism (see Yayon et ah, 1991, Cell 4: 841-848). Angiogenesis is also associated with a number of other pathological conditions, including the growth, proliferation, and metastasis of various tumors; diabetic retinopathy, retrolental fibroplasia, neovascular glaucoma, psoriasis, angiofibromas, immune and non- immune inflammation including rheumatoid arthritis, capillary proliferation within atherosclerotic plaques, hemangiomas, endometriosis and Kaposi's sarcoma. Thus, it would be desirable to inhibit angiogenesis in these and other instances, and the heparin binding and neutralization activities of BPI are useful to that end. Several other heparin neutralizing proteins are also known to inhibit angiogenesis. For example, protamine is known to inhibit tumor-associated angiogenesis and subsequent tumor growth [see Folkman et ah , 1992, Inflammation: Basic Principles and Clinical Correlates, 2d ed. , (Galin et a , eds., Review Press, N.Y.), Ch. 40, pp. 821-839] A second heparin neutralizing protein, platelet factor IV, also inhibits angiogenesis (i.e. , is angiostatic). Collagenase inhibitors are also known to inhibit angiogenesis (see Folkman et ah, 1992, ibid.) Another known angiogenesis inhibitor, thrombospondin, binds to heparin with a repeating serine/tryptophan motif instead of a basic amino acid motif (see Guo et a , 1992, J. Biol. Chem. 267: 19349-19355). Another utility of BPI involves pathological conditions associated with chronic inflammation, which is usually accompanied by angiogenesis. One example of a human disease related to chronic inflammation is arthritis, which involves inflammation of peripheral joints. In rheumatoid arthritis, the inflammation is immune-driven, while in reactive arthritis, inflammation is associated with infection of the synovial tissue with pyogenic bacteria or other infectious agents. Folkman et ah, 1992, supra, have also noted that many types of arthritis progress from a stage dominated by an inflammatory infiltrate in the joint to a later stage in which a neovascular pannus invades the joint and begins to destroy cartilage. While it is unclear whether angiogenesis in arthritis is a causative component of the disease or an epiphenomenon, there is evidence that angiogenesis is necessary for the maintenance of synovitis in rheumatoid arthritis. One known angiogenesis inhibitor, AGM1470, has been shown to prevent the onset of arthritis and to inhibit established arthritis in collagen-induced arthritis models (Peacock et ah, 1992, J. Exp. Med. 175: 1135-1138). While nonsteroidal anti-inflammatory drugs, corticosteroids and other therapies have provided treatment improvements for relief of arthritis, there remains a need in the art for more effective therapies for arthritis and other inflammatory diseases. There continues to exist a need in the art for new products and methods for use as bactericidal agents and endotoxin neutralizing agents, and for heparin neutralization and inhibition of angiogenesis (normal or pathological). One avenue of investigation towards fulfilling this need is the determination of the functional domains of the BPI protein specifying each of these biological activities. Advantageous therapeutic embodiments would therefore comprise BPI functional domain peptides having one or more than one of the activities of BPI. SUMMARY OF THE INVENTION This invention provides small, readily-produced peptides having an amino acid sequence that is the amino acid sequence of a BPI functional domain or a subsequence thereof and variants of the sequence or subsequence having at least one of the biological activities of BPI, such as heparin binding, heparin neutralization, LPS binding, LPS neutralization or bactericidal activity. The functional domains of BPI discovered and described herein include: domain I, encompassing the amino acid sequence of BPI from about amino acid 17 to about amino acid 45; domain π, encompassing the amino acid sequence of BPI from about amino acid 65 to about amino acid 99; and domain HI, encompassing the amino acid sequence of BPI from about amino acid 142 to about amino acid 169. Thus, the BPI functional domain peptides are based on the amino-terminal portion of human BPI. The peptides of the invention include linear and cyclized peptides, and peptides that are linear, cyclized and branched-chain combinations of particular BPI functional domain amino acid sequences or subsequences thereof and variants of the sequence or subsequence. Combination peptides include peptides having the sequence or subsequence and variants of the sequence or subsequence of the same or different functional domains of BPI that are covalently linked together. Specifically included are combinations from two to about 10 peptides of any particular sequence or subsequence thereof and variants of that sequence or subsequence. The invention also provides peptides having additional biological activities distinct from the known biological activities of BPI, including but not limited to bactericidal activity having an altered target cell species specificity. Peptides having particular biological properties of BPI that are enhanced or decreased compared with the biological properties of BPI are also provided. The peptides of the invention include linear and cyclized peptides, and peptides that are linear, cyclized and branched-chain amino acid substitution and additional variants of particular BPI functional domain amino acid sequences or subsequences thereof. For the substitution variants, amino acid residues at one or more positions in each of the peptides are replaced with a different amino acid residue (including atypical amino acid residues) from that found in the corresponding position of the BPI functional domain from which the specific peptide is derived. For the addition variants, peptides may include up to about a total of 10 additional amino acids, covalently linked to either the amino-terminal or carboxyl-terminal extent, or both, of the BPI functional domain peptides herein described. Such additional amino acids may duplicate amino acids in BPI contiguous to a functional domain or may be unrelated to BPI amino acid sequences and may include atypical amino acids. Linear, cyclized, and branched-chain combination embodiments of the amino acid substitution and addition variant peptides are also provided as peptides of the invention, as are cyclized embodiments of each of the aforementioned BPI functional domain peptides. In addition, peptides of the invention may be provided as fusion proteins with other functional targeting agents, such as immunoglobulin fragments. Addition variants include derivatives and modifications of amino acid side chain chemical groups such as amines, carboxylic acids, alkyl and phenyl groups. The invention provides pharmaceutical compositions for use in treating mammals for neutralizing endotoxin, killing Gram-negative and Gram-positive bacteria and fungi, neutralizing the anti-coagulant properties of heparin, inhibiting angiogenesis, inhibiting tumor and endothelial cell proliferation, and treating chronic inflammatory disease states. The pharmaceutical compositions comprise unit dosages of the BPI peptides of this invention in solid, semi-solid and liquid dosage forms such as tablet pills, powder, liquid solution or suspensions and iηjectable and infusible solutions. This invention provides peptides having an amino acid sequence which is the amino acid sequence of human BPI from about position 17 to about position 45 comprising functional domain I, having the sequence: Domain I ASQQGTAALQKELKRIKIPDYSDSFKIKH (SEQ ID NO:l); and subsequences thereof which have biological activity, including but not limited to one or more of the activities of BPI, for example, bactericidal activity, LPS binding, LPS neutralization, heparin binding or heparin neutralization. Also provided in this aspect of the invention are peptides having substantially the same amino acid sequence of the functional domain I peptides having the amino acid sequence of BPI from about position 17 to about position 45 or subsequences thereof. Additionally, the invention provides peptides which contain two or more of the same or different domain I peptides or subsequence peptides covalently linked together. This invention provides peptides having an amino acid sequence which is the amino acid sequence of human BPI from about position 65 to about position 99 comprising functional domain π, having the sequence: Domain π SSQISMVPNVGLKFSISNANIKISGKWKAQKRFLK (SEQ ID NO:6); and subsequences thereof which have biological activity, including but not limited to one or more of the activities of BPI, for example, bactericidal activity, LPS binding, LPS neutralization, heparin binding or heparin neutralization. Also provided in this aspect of the invention are peptides having substantially the same amino acid sequence of the functional domain π peptides having the amino acid sequence of BPI from about position 65 to about position 99 or subsequences thereof. Additionally, the invention provides peptides which contain two or more of the same or different domain π peptides or subsequence peptides covalently linked together. The invention also provides peptides having an amino acid sequence which is the amino acid sequence of human BPI from about position 142 to about position 169 comprising functional domain HI, having the sequence: Domain m VHVfflSKSKVGWLIQLFHKKIESALRNK (SEQ ID NO: 12); and subsequences thereof which have biological activity, including but not limited to one or more of the activities of BPI, for example, bactericidal activity, LPS binding, LPS neutralization, heparin binding or hepaiin neutralization. Also provided in this aspect of the invention are peptides having substantially the same amino acid sequence of the functional domain III peptides having the amino acid sequence of BPI from about position 142 to about position 169 or subsequences thereof. Additionally, the invention provides peptides which contain two or more of the same or different domain HI peptides or subsequence peptides covalently linked together. Also provided by this invention are interdomain combination peptides, wherein two or more peptides from different functional domains or subsequences and variants thereof are covalently linked together. Linear, cyclized and branched-chain embodiments of these interdomain combination peptides are provided. The peptides of this invention have as one aspect of their utility at least one of the known activities of BPI, including LPS binding, LPS neutralization, heparin binding, heparin neutralization and bactericidal activity against Gram- negative bacteria. Additionally and surprisingly, some of the peptides of this invention have utility as bactericidal agents against Gram-positive bacteria. Another surprising and unexpected utility of some of the peptides of this invention is as fungicidal agents. Peptides of this invention provide a new class of antibiotic molecules with the dual properties of neutralizing endotoxin and killing the endotoxin-producing bacteria, useful in the treatment of mammals suffering from diseases or conditions caused by Gram-negative bacteria. Peptides of this invention that retain this dual activity and additionally have an increased antibiotic spectrum represent an additional new class of antimicrobial agents. In addition, peptides of the invention provide a class of antimicrobial agents useful in the treatment of infections by microbial strains that are resistant to traditional antibiotics but are sensitive to the permeability-increasing antimicrobial activity of peptides of the invention. The invention also provides pharmaceutical compositions of the peptides of the invention comprising the peptides or combinations of the peptides in a pharmaceutically-acceptable carrier or diluent, both per se and for use in methods of treating pathological or disease states or for other appropriate therapeutic uses. Methods of using these pharmaceutical compositions for the treatment of pathological or disease states in a mammal, including humans, are also provided by the invention. Also provided by the invention are uses of BPI functional domain peptide for the manufacture of medicaments for a variety of therapeutic applications. Specific preferred embodiments of the present invention will become evident from the following more detailed description of certain preferred embodiments and the claims. BRIEF DESCRIPTION OF THE DRAWINGS Figures la and lb depict HPLC absorbance spectra for cyanogen bromide and proteolytic fragments of rBPI^; Figure 2 is a graph of LAL inhibition assay results for proteolytic fragments of TEPI^, Figure 3 is a graph of a heparin binding assay results using 15-mer BPI peptides; Figure 4 is a graph of a Limulus Amoebocyte Lysate (LAL) inhibition assay results using 15-mer BPI peptides; Figure 5 is a graph of a radial diffusion bactericidal assay results using 15-mer BPI peptides; Figure 6 is a graph showing the effect of BPI functional domain peptides in a heparin binding assay; Figures 7a and 7b are graphs showing the effects of BPI functional domain peptides on ATUl/heparin inhibition of thrombin; Figures 8a and 8b are graphs showing the results of BPI functional domain peptides in an LAL inhibition assay; Figures 9a, 9b, 9c, and 9d are graphs showing the results of BPI functional domain peptides in radial diffusion bactericidal assays; Figures 9e and 9f are graphs showing the results of BPI functional domain peptides in E. coli broth assays; Figures 10a, 10b, 10c, lOd and lOe are graphs showing the results of BPI functional domain combination peptides in radial diffusion bactericidal assays; Figures 11a, lib, lie, lid, lie, llf, llg, llh and Hi are graphs showing the results of BPI functional domain peptides in radial diffusion bactericidal assays; Figures llj and Ilk are graphs showing the results of BPI functional domain peptides in bactericidal assays on bacterial cells growing in broth media; Figure 111 is a graph showing the results of BPI functional domain peptide BPI.30 in bactericidal assays performed in human serum; Figures 11m and lln are graphs showing the results of BPI functional domain peptides in radial diffusion bactericidal assays using Gram-positive bacteria; Figure llo is a graph showing the results of BPI functional domain peptides in radial diffusion bactericidal assays in comparison with gentamicin and vancomycin using S. aureus cells; Figures lip and llq are graphs showing the results of BPI functional domain peptides in cytotoxicity assays using C. albicans cells growing in broth media; Figures 12a, 12b, 12c, 12d, 12e, 12f, and 12g are graphs showing the results of a heparin neutralization assay using BPI functional domain peptides; Figure 13 is a schematic diagram of the structure of BPI domain π peptide BPI.2 (amino acid sequence 85-99 of the BPI sequence, SEQ ID NO:7); Figure 14 is a schematic diagram of the structure of BPI domain HI peptide BPI.11 (amino acid sequence 148-161 of the BPI sequence, SEQ ID NO: 13); Figures 15a, 15b, 15c, 15d and 15e are graphs showing the results of heparin binding assays using BPI functional domain substitution peptides; Figure 16 is a graph showing the results of heparin binding experiments using a variety of BPI functional domain peptides; Figures 17a and 17b are graphs of the results of Lipid A binding competition assays between synthetic BPI functional domain peptides and radiolabeled rBP^; Figure 18 is a graph of the results of Lipid A binding competition assays between synthetic BPI.10 peptide and radiolabeled rBPI^ in blood or phosphate buffered saline; Figure 19 is a graph of the results of Lipid A binding competition assays between synthetic BPI peptides BPI.7, BPI.29 and BPI.30 versus radiolabeled rBPI^; Figures 20a and 20b are graphs of the results of Lipid A binding competition assays between BPI functional domain peptides and radiolabeled rLBP ; Figure 21 is a graph of the results of radiolabeled RaLPS binding experiments using BPI functional domain peptides pre-bound to HUVEC cells; Figures 22a, 22b, 22c, 22d, 22e. 22f, 22g, and 22h are graphs showing the various parameters affecting a cellular TNF cytotoxicity assay measuring the LPS neutralization activity of BPI; Figures 23a, 23b and 23c are graphs showing the dependence of NO production on the presence of 7-interferon and LBP in LPS-stimulated RAW 264.7 cells and inhibition of such NO production using Figures 24a, 24b, 24c, 24d, 24e, and 24f are graphs showing LPS neutralization by BPI functional domain peptides reflected in their capacity to inhibit NO production by RAW 264.7 cells stimulated by zymosan or LPS; Figure 24g is a graph showing the IC 50 values of synthetic BPI peptides for inhibition of LPS- or zymosan-stimulated NO production by RAW 264.7 cells; Figure 25 is a schematic of rBPI^ showing three functional domains; Figure 26a is a graph showing the dependence of LPS-mediated inhibition of RAW 264.7 cell proliferation on the presence of rLBP; Figures 26b and 26c are graphs showing patterns of BPI functional domain peptides using the assay of Example 20D; Figure 27 is a graph showing a comparision of TNF inhibition in whole blood by various BPI functional domain peptides using the assay of Example 20E; and Figure 28 is a graph showing the results of the thrombin clotting time assay described in Example 20G using various BPI functional domain peptides. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS This invention provides peptides having an amino acid sequence that is the amino acid sequence of at least one functional domain or subsequence thereof and variants of the sequence or subsequence of BPI. For the purposes of this invention, the term "functional domain" is intended to designate a region of the amino acid sequence of BPI that contributes to the total biological activity of the protein. These functional domains of BPI are defined by the activities of proteolytic cleavage fragments, overlapping 15-mer peptides and other synthetic peptides. Domain I is defined as the amino acid sequence of BPI comprising from about amino acid 17 to about amino acid 45. Peptides based on this domain are moderately active in both the inhibition of LPS-induced LAL activity and in heparin binding assays, and do not exhibit significant bactericidal activity. Domain π is defined as the amino acid sequence of BPI comprising from about amino acid 65 to about amino acid 99. Peptides based on this domain exhibit high LPS and heparin binding capacity and are bactericidal. Domain HI is defined as the amino acid sequence of BPI comprising from about amino acid 142 to about amino acid 169. Peptides based on this domain exhibit high LPS and heparin binding activity and are bactericidal. The functional domains as herein defined include the continuous domains I, π and III, i.e. , domains comprised of a continuous portion of the BPI amino acid sequence. However, the invention also includes peptides comprising portions of BPI which are not continuous, i.e. , that are separated in the BPI sequence. It is recognized that some non-continuous stretches of amino acid sequence may be folded in the native protein to make such amino acid regions contiguous or in proximity, which structure can be mimicked in the peptides of the invention by covalently linking together peptides from non-continuous regions. Peptides containing non-continuous regions of BPI amino acid sequence are one example of combination peptides provided by the invention. For the purposes of this invention, combination peptides are intended to include linear, cyclized or branched-chain peptides comprised of two or more peptides having an amino acid sequence from the same or different functional domains of BPI and subsequences thereof. Specifically encompassed in this definition are combinations containing from two to about 10 functional domain peptides or subsequence thereof, preferably combinations of two or three functional domain peptides (for example, homodimers, homotrimers, heterodimers and heterotrimers). Each of the component peptides comprising such combinations may have an amino acid sequence from any particular BPI functional domain amino acid sequence or subsequence thereof. For purposes of this invention, the term "a biological activity of BPI" is intended to include, but is not limited to the biological activities of a human bactericidal/permeability-increasing protein (BPI), including, for example, a recombinant BPI holoprotein such rBPI (SEQ ID NO: 69), an amino-terminal fragment of BPI such as rBPI^, and mutated amino-terminal fragments of BPI such as rBPI 21 Δcys (designated rBPI (1 - 193) ala 132 in copending and co- assigned U.S. Patent Application Serial No. 08/013,801, filed February 2, 1993, incorporated by reference). As disclosed in copending and co-assigned U.S. Patent Application Serial No. 08/093,202, incorporated by reference, rBPI has been produced having the sequence set out as SEQ ID NO: 69 as shown in Gray et a (supra) except that valine at position 151 is specified by GTG rather than GTC, and residue 185 is glutamic acid (specified by GAG) rather than lysine (specified by AAG). In addition, rBPI-y (see also, Gazzano- Santoro et a , 1992, Infect. Immun. 60: 4754-4761) has been produced using an expression vector containing the 31-residue signal sequence and the first 199 amino acids of the sequence of rBPI with the exceptions from the Gray et ah (supra) sequence as noted above. Such biological activities include LPS binding, LPS neutralization, heparin binding and heparin neutralization, and bactericidal activity. Specifically included is a biological activity of any peptide of this invention that is between 0.1 and 10 times the activity of BPI or of a corresponding peptide encompassing a corresponding functional domain of BPI. Also expressly included in this definition of the "biological activity of BPI" is a biological activity, for example bactericidal activity, that is qualitatively different than the activity of BPI or the corresponding peptide encompassing the entire corresponding domain of BPI. For example, such qualitative differences include differences in the spectrum of bacteria or other microorganisms against which the peptide is effective, relative to the amino acid sequence of the corresponding functional domain of BPI. This definition thus encompasses peptide activities, such as bactericidal activity against Gram- positive bacteria and fungicidal activity, not previously reported for BPI. The invention provides peptides each of which has an amino acid sequence that is the amino acid sequence of one of the functional domains of human BPI or a subsequence thereof. Embodiments of such peptides include the following exemplary domain I peptides [single-letter abbreviations for amino acids can be found in G. Zubay, Biochemistry (2d. ed.), 1988 (MacMillen Publishing: N.Y.), p.33]: BPI.l QQGTAALQKELKRIK (SEQ ID NO:4); BPI.4 LQKELKRIKIPDYSDSFKIKHL (SEQ ID NO:3); BPI.14 GTAALQKELKRDOPDYSDSFKIKHLGKGH (SEQ ID NO:2); and BPI.54 GTAALQKELKRIKIP (SEQ ID NO:5); the following exemplary domain π peptides: BPI.2 KISGKWKAQKRFLK (SEQ ID NO:7); BPI.3 NVGLKFSISNANIKISGKWKAQKRFLK (SEQ ID NO: 11); and BPI.8 KWKAQKRFLK (SEQ ID NO: 8); and the following exemplary domain HI peptides: BPI.5 VHVfflSKSKVGWLIQLFHKKIE (SEQ ID NO: 67); BPI.11 KSKVWLIQLFHKK (SEQ ID NO: 13) ; BPI.12 SVHVfflSKSKVGWLIQLFHKKIESALRNK (SEQ ID NO: 14); BPI.13 KSKVGWLIQLFHKK (SEQ ID NO: 15); and BPI.55 GWLIQLFHKKIESALRNKMNS (SEQ ID NO:61). It will be recognized that BPI.14, BPI.12 and BPI.55 are examples of addition variants. The invention also provides linear and branched-chain combinations of the same or different peptides, wherein each of the peptides of the combination has an amino acid sequence that is the amino acid sequence of one of the functional domains of human BPI or a subsequence thereof. Embodiments of such peptides include the following exemplary combination domain π peptides: BPI.9 KRFLKKWKAQKRFLK (SEQ ID NO:51); BPI.7 KWKAQKRFLKKWKAQKRFLK (SEQ ID NO:54); BPI.10.1 KRFLKKWKAQKRFLKKWKAQKRFLK (SEQ ID NO:55); and BPI.10.2 QKRFLKKWKAQKRFLKKWKAQKRFLK (SEQ ID NO: 65); and the following exemplary branched-chain domain π peptide: MAP.1 (/3-alanyl-Nα,Ne-substituted-[Nα,Ne(BPI.2)lysyl]lysine); and the following exemplary combination domain HI peptide: BPI.29 KSKVGWLIQLFHKKKSKVGWLIQLFHKK (SEQ ID ΝO:56); and the following exemplary branched-chain domain IH peptide: MAP.2 (|3-alanyl-Nα,Ne-substituted-[Nα,Ne(BPI.13)lysyl]lysine); and the following exemplary domain ϋ-domain UI interdomain combination peptides: BPI.30 KWKAQKRFLKKSKVGWLIQLFHKK (SEQ ID ΝO:52); BPI.63 IKISGKWKAQKRFLKKSKVGWLIQLFHKK (SEQ ID NO:53); and BPI.74 KSKVGWLIQLFHKKKWKAQKRFLK (SEQ ID No.:70). Amino acid substitution variants are also provided, wherein the amino acid residue at one or more positions in each of the peptides is a residue different from the amino acid found in the corresponding position of the BPI functional domain from which that specific peptide is derived. For example, in one embodiment of this aspect of the invention, one position in the peptide is substituted with an alanine residue for the amino acid found at the corresponding position in the BPI amino acid sequence. In other embodiments, one position in the peptide is substituted with e.g. , a phenylalanine, leucine, lysine or tryptophan residue for the amino acid found at the corresponding position in the BPI amino acid sequence. Embodiments of these peptides include the following exemplary substitution domain π peptides: BPI.15 AKISGKWKAQKRFLK (SEQ ID NO: 16) BPI.16 IAISGKWKAQKRFLK (SEQ ID NO: 17) BPI.17 KASGKWKAQKRFLK (SEQ ID NO: 18) BPI.18 IKIAGKWKAQKRFLK (SEQ ID NO: 19) BPI.19 IKISAKWKAQKRFLK (SEQ ID NO:20) BPI.20 IKISGAWKAQKRFLK (SEQ ID NO:21) BPI.21 IKISGKAKAQKRFLK (SEQ ID NO:22) BPI.22 IKISGKWAAQKRFLK (SEQ ID NO:23) BPI.23 IKISGKWKAAKRFLK (SEQ ID NO:24) BPI.24 IKISGKWKAQARFLK (SEQ ID NO:25) BPI.25 IKISGKWKAQKAFLK (SEQ ID NO:26) BPL26 IKISGKWKAQKRALK (SEQ ID NO:27) BPI.27 IKISGKWKAQKRFAK (SEQ ID NO:28) BPI.28 IKISGKWKAQKRFLA (SEQ ID NO:29) BPI.61 IKISGKFKAQKRFLK (SEQ ID NO:48) BPI.73 IKISGKWKAQFRFLK (SEQ ID NO:62) BPI.77 IKISGKWKAQWRFLK (SEQ ID NO:72) BPI.79 IKISGKWKAKKRFLK (SEQ ID NO:73) and BPI.81 IKISGKWKAFKRFLK (SEQ ID NO:75); and the following exemplary substitution domain m peptides: BPI.31 ASKVGWLIQLFHKK (SEQ ID NO:33) BPI.32 KAKVGWLIQLFHKK (SEQ ID NO:34) BPI.33 KSAVGWLIQLFHKK (SEQ ID NO:35) BPI.34 KSKAGWLIQLFHKK (SEQ ID NO:36) BPI.35 KSKVAWLIQLFHKK (SEQ ID NO:37) BPI.36 KSKVGALIQLFHKK (SEQ ID NO: 38) BPI.37 KSKVGWAIQLFHKK (SEQ ID NO:39) BPI.38 KSKVGWLAQLFHKK (SEQ ID NO:40) BPI.39 KSKVGWLIALFHKK (SEQ ID NO:41) BPI.40 KSKVGWLIQAFHKK (SEQ ID NO:42) BPI.41 KSKVGWLIQLAHKK (SEQ ID NO:43) BPI.42 KSKVGWLIQLFAKK (SEQ ID NO:44) BPI.43 KSKVGWLIQLFHAK (SEQ ID NO:45) BPI.44 KSKVGWLIQLFHKA (SEQ ID NO:46) BPI.82 KSKVGWLIQLWHKK (SEQ ID NO:76) BPI.85 KSKVLWLIQLFHKK (SEQ ID NO:79) BPI.86 KSKVGWLILLFHKK (SEQ ID NO: 80) BPI.87 KSKVGWLIQLFLKK (SEQ ID NO:81) BPI.91 KSKVGWLIFLFHKK (SEQ ID NO:86) BPI.92 KSKVGWLIKLFHKK (SEQ ID NO:87) BPI.94 KSKVGWLIQLFFKK (SEQ ID NO: 89) BPI.95 KSKVFWLIQLFHKK (SEQ ID NO:90) BPI.96 KSKVGWLIQLFHKF (SEQ ID NO:91) and BPI.97 KSKVKWLIQLFHKK (SEQ ID NO:92). A particular utility of such single amino acid-substituted BPI functional domain peptides provided by the invention is to identify critical residues in the peptide sequence, whereby substitution of the residue at a particular position in the amino acid sequence has a detectable effect on at least one of the biological activities of the peptide. Expressly encompassed within the scope of this invention are embodiments of the peptides of the invention having substitutions at such critical residues so identified using any amino acid, whether naturally- occurring or atypical, wherein the resulting substituted peptide has biological activity as defined herein. Substituted peptides are also provided that are multiple substitutions, i.e. , where two or more different amino acid residues in the functional domain amino acid sequence are each substituted with another amino acid. For example, in embodiments of such doubly-substituted peptides, both positions in the peptide are substituted e.g. , with alanine, phenylalanine or lysine residues for the amino acid found at the corresponding positions in the BPI amino acid sequence. Examples of embodiments of these peptides include the multiply substituted domain π peptides: BPI.45 IKISGKWKAAARFLK (SEQ ID NO:31) BPI.56 KISGKWKAKQRFLK (SEQ ID NO:47) BPI.59 IKISGAWAAQKRFLK (SEQ ID NO:30) BPI.60 IAISGKWKAQKRFLA (SEQ ID NO:32) and BPI.88 IKISGKWKAFFRFLK (SEQ ID NO: 82); and the exemplary multiply substituted domain HI peptide: BPI.100 KSKVKWLIKLFHKK (SEQ ID NO:94); and the following exemplary multiply substituted domain II substitution combination peptide: BPI.101 KSKVKWLKLFFKFKSKVKWLIKLFFKF (SEQ ID NO:95); and the following exemplary multiply substituted domain Il-domain IH interdomain substitution combination peptide: BPI.102 KWKAQFRFLKKSKVGWLILLFHKK (SEQ ID NO:96). Another aspect of such amino acid substitution variants are those where the substituted amino acid residue is an atypical amino acid. Specifically encompassed in this aspect of the peptides of the invention are peptides containing D-amino acids, modified or non-naturally-occurring amino acids, and altered amino acids to provide peptides with increased stability, potency or bioavailability. Embodiments of these peptides include the following exemplary domain π peptides with atypical amino acids: BPI.66 IKISGKW D KAQKRFLK (SEQ ID NO:49) BPI.67 παSGKA 0 . α→uιphthyD KAQKRFLK (SEQ ID NO:50) BPI.70 mSGKA H3 . pyridyI) KAQKRFLK (SEQ ID NO:63) BPI.71 A Q A D IKISGKWKAQKRFLK (SEQ ID NO:66) BPI.72 IKISGKWKAQKRA β . (3 . pyri a yI) LK (SEQ ID NO:64) BPI.76 IKISGKWKAQF D RFLK (SEQ ID NO:71) and BPI.90 παSGKA wl . nιphthyI) KAFFRFLK (SEQ ID NO:85); the exemplary domain m peptide with atypical amino acids: BPI.83 KSKVGAø_ (1 .^ hftyD LIQLFHKK (SEQ ID NO:77); and the exemplary domain π-domain HI interdomain combination peptides with atypical amino acids: BPI.93 IKISGKA wl . naphthyI) KAQFRFLKKSKVGWLIQLFHKK (SEQ ID NO: 88); and BPI.98 παSGKA^ (1 . ωphthyI) KAQFRFLKKSKVGWLIFLFHKK (SEQ ID NO: 83). Linear and branched-chain combination embodiments of the amino acid substitution variant peptides, which create multiple substitutions in multiple domains, are also an aspect of this invention. Embodiments of these peptides include the following exemplary combination/substitution domain II peptides: BPI.46 KWKAAARFLKKWKAQRFLK (SEQ ID NO:57) BPI.47 KWKAQKRFLKKWKAAARFLK (SEQ ID NO:58) BPI.48 KWKAAARFLKKWAAAKRFLK (SEQ ID NO:59) BPI.69 KWKAAARFLKKWKAAARFLKKWKAAARFLK (SEQ ID NO: 60); and BPI.99 KWKAQWRFLKKWKAQWRFLKKWKAQWRFLK (SEQ ID NO:93). Dimerized and cyclized embodiments of each of the aforementioned BPI functional domain peptides are also provided by this invention. Embodiments of these peptides include the following exemplary cysteine-modified domain π peptides: BPI.58 CIKISGKWKAQKRFLK (SEQ ID NO: 9); BPI.65(red) CIKISGKWKAQKRFLKC (SEQ ID NO:68); and S - S BPI.65(ox.) CIKISGKWKAQKRFLKC (SEQ ID NO: 10). BPI functional domain peptides described herein are useful as potent anti-bacterial agents for Gram-negative bacteria and for neutralizing the adverse effects of LPS associated with the cell membranes of Gram-negative bacteria. The peptides of the invention have, in varying amounts, additional activities of BPI, including activities not directly associated with the Gram-negative bacterial infection, such as heparin binding and neutralization. Peptides provided by this invention also may have biological activities distinct from the known biological activities of BPI. For example, some embodiments of the peptides of the invention surprisingly have been found to have a biological target range for bactericidal activity that is broader than BPI and exhibits bactericidal activity against Gram-positive as well as Gram-negative bacteria. Some embodiments of the invention have surprisingly been found to have fungicidal activity. Thus, the invention advantageously provides peptides having amino acid sequences of the biologically functional domains of BPI having distinct antimicrobial activities. Peptides of this invention that possess the dual anti¬ bacterial and anti-endotoxic properties of BPI, including those with an increased antibiotic spectrum, represent a new class of antibiotic molecules. BPI functional domain peptides of the invention will have biological therapeutic utilities heretofor recognized for BPI protein products. For example, co-owned, copending U.S. Patent Application Serial No. 08/188,221 filed January 24, 1994, addresses use of BPI protein products in the treatment of humans exposed to Gram-negative bacterial endotoxin in circulation. Co- owned, copending U.S. Patent Application Serial No. 08/031,145 filed March 12, 1993 addresses administration of BPI protein products for treatment of mycobacterial diseases. Co-owned, copending U.S. Patent Application Serial No. 08/132,510, filed October 5, 1993, addresses use of BPI protein products in the treatment of conditions involving depressed reticuloendothelial system function. Co-owned, copending U.S. Patent Application Serial No. 08/125,651, filed September 22, 1993, addresses synergistic combinations of BPI protein products and antibiotics. Co-owned, copending U.S. Patent Application Serial No. 08/093,201 filed July 14, 1993, addresses methods of potentiating BPI protein product bactericidal activity by administration of LBP protein products. Co-owned, copending U.S. Patent Application Serial No. 08/031,144 filed March 12, 1993, addresses administration of BPI protein products for treatment of Helicobacterial infections. The disclosures of the above applications are specifically incorporated by reference herein for the purpose of exemplifying therapeutic uses for BPI functional domain peptides of the invention. The BPI functional domain peptides of the invention also have therapeutic utility for the treatment of pathological conditions and disease states as disclosed in the above identified U.S. Patent Application Serial Nos. 08/030,644, 08/093,202 and Oδ/183,222 parent applications. BPI functional domain peptides of the invention are thus useful in methods for: neutralizing the anti-coagulant effect of heparin; inhibiting angiogenesis (especially angiogenesis associated with ocular retinopathy); inhibiting endothelial cell proliferation (especially endometriosis and proliferation associated with implantation of fertilized ova); inhibiting malignant tumor cell proliferation (especially Kaposi's sarcoma proliferation); treating chronic inflammatory disease states (such as arthritis and especially reactive and rheumatoid arthritis); treating Gram-negative bacterial infection and the sequelae thereof; treating the adverse effects (such as increased cytokine production) of Gram-negative endotoxin in blood circulation; killing Gram-negative bacteria; treating adverse physiological effects associated with depressed reticuloendothelial system function (especially involving depressed function of Kupffer cells of the liver such as results from physical, chemical and biological insult to the liver); treating, in synergistic combination with antibiotics (such as gentamicin, polymyxin B and cefamandole nafate) Gram-negative bacterial infection and the sequelae thereof; killing Gram-negative bacteria in synergistic combination with antibiotics; treating, in combination with LBP protein products, Gram-negative bacterial infection and the sequelae thereof; killing Gram-negative bacteria in combination with LBP protein products; treating, alone or in combination with antibiotics and/or bismuth, Mycobacteria infection (especially infection by M. tuberculosis, M. leprae and M. avium); treating adverse physiological effects (such as increased cytokine production) of lipoarabinomannan in blood circulation; decontaminating fluids (such as blood, plasma, serum and bone marrow) containing lipoarabinomannan; and, treating disease states (such as gastritis and peptic, gastric and duodenal ulcers) associated with infection by bacteria of the genus Helicobacter. The present invention also provides pharmaceutical compositions for oral, parenteral, topical and aerosol administration comprising BPI functional domain peptides in amounts effective for the uses noted above and especially compositions additionally comprising pharmaceutically acceptable diluents, adjuvants or carriers. With respect to uses of BPI functional domain peptides in combination with LBP protein products, as used herein, "LBP protein product" includes naturally and recombinantly product lipopolysaccharide binding protein; natural, synthetic, and recombinant biologically active polypeptide fragments and derivatives of lipopolysaccharide binding protein; and biologically active polypeptide analogs, including hybrid fusion proteins, of either LBP or biologically active fragments thereof. LBP protein products useful according to the methods of the present invention include LBP holoprotein which can be produced by expression of recombinant genes in transformed eucaryotic host cells such as described in co-owned and copending U.S. Patent Application Serial No. 08/079,510 filed June 17, 1993 and designated rLBP. Also described in that application are preferred LBP protein derivatives which lack CD14-mediated inflammatory properties and particularly the ability to mediate LPS activity through the CD14 receptor. Such LBP protein products are preferred for use according to the present invention because excessive CD 14- mediated immunostimulation is generally considered undesirable, and is particularly so in subjects suffering from infection. Preferred LBP protein derivatives are characterized as amino-terminal fragments having a molecular weight of about 25kD. Most preferred are LBP amino-terminal fragments characterized by the amino acid sequence of the first 197 amino acids of the amino-terminus of LBP, as set out in SEQ ID NOS:97 and 98, designated rLBPjs, the production of which is described in previously- noted co-owned and copending U.S. Patent Application Serial No. 08/079,510. It is contemplated that LBP protein derivatives considerably smaller than 25 kD and comprising substantially fewer than the first 197 amino acids of the amino- terminus of the holo-LBP molecule are suitable for use according to the invention provided they retain the ability to bind to LPS. Moreover, it is contemplated that LBP protein derivatives comprising greater than the first 197 amino acid residues of the holo-LBP molecule including amino acids on the carboxy-terminal side of first 197 amino acids of the rLBP as disclosed in SEQ ID NOS: 97 and 98 will likewise prove useful according to the methods of the invention provided they lack an element that promotes CD14-mediated immunostimulatory activity. It is further contemplated that those of skill in the art are capable of making additions, deletions and substitutions of the amino acid residues of SEQ ID NOS: 97 and 98 without loss of the desired biological activities of the molecules. Still further, LBP protein products may be obtained by deletion, substitution, addition or mutation, including mutation by site-directed mutagenesis of the DNA sequence encoding the LBP holoprotein, wherein the LBP protein product maintains LPS-binding activity and lacks CD14-mediated immunostimulatory activity. Specifically contemplated are LBP hybrid molecules and dimeric forms which may result in improved affinity of LBP for bacteria and/or increased stability in vivo. These include LBP/BPI hybrid proteins and LBP-Ig fusion proteins. Such hybrid proteins further include those using human gamma 1 or gamma 3 hinge regions to permit dimer formation. Other forms of dimer contemplated to have enhanced serum stability and binding affinity include fusions with Fc lacking the CH 2 domain, or hybrids using leucine or helix bundles. BPI functional domain peptides of the invention may be generated and/or isolated by any means known in the art, including by means of recombinant production. Co-owned U.S. Patent No. 5,028,530, issued July 2, 1991, co- owned U.S. Patent No. 5,206,154, issued April 27, 1993, and co-owned, copending U.S. Patent Application Serial No. 08/010,676, filed January 28, 1993, all of which are hereby incorporated by reference, disclose novel methods for the recombinant production of polypeptides, including antimicrobial peptides. Additional procedures for recombinant production of antimicrobial peptides in bacteria have been described by Piers et ah, 1993, Gene 134: 7-13. Co-owned, copending U.S. Patent Application Serial No. 07/885,501, filed May 19, 1992, and a continuation-in-part thereof, U.S. Patent Application Serial No. 08/072,063, filed May 19, 1993 which are both hereby incorporated by reference, disclose novel methods for the purification of recombinant BPI expressed in and secreted from genetically transformed mammalian host cells in culture and discloses how one may produce large quantities of recombinant BPI suitable for incorporation into stable, homogeneous pharmaceutical preparations. BPI functional domain peptides may also be advantageously produced using any such methods. Those of ordinary skill in the art are able to isolate or chemically synthesize a nucleic acid encoding each of the peptides of the invention. Such nucleic acids are advantageously utilized as components of recombinant expression constructs, wherein the nucleic acids are operably linked with transcriptional and/or translational control elements, whereby such recombinant expression constructs are capable of expressing the peptides of the invention in cultures of prokaryotic, or preferably eukaryotic cells, most preferably mammalian cells, transformed with such recombinant expression constructs. Peptides of the invention may be advantageously synthesized by any of the chemical synthesis techniques known in the art, particularly solid-phase synthesis techniques, for example, using commercially-available automated peptide synthesizers. Such peptides may also be provided in the form of combination peptides, wherein the peptides comprising the combination are linked in a linear fashion one to another and wherein a BPI sequence is present repeatedly in the peptide, with or without separation by "spacer" amino acids allowing for selected conformational presentation. Also provided are branched- chain combinations, wherein the component peptides are covalently linked via functionalities in amino acid sidechains of the amino acids comprising the peptides. Functional domain peptides of this invention can be provided as recombinant hybrid fusion proteins comprising BPI functional domain peptides and at least a portion of at least one other polypeptide. Such proteins are described, for example, by Theofan et a in co-owned, copending U.S. Patent Application Serial No. 07/885,911, filed May 19, 1992, and a continuation-in- part application thereof, U.S. Patent Application Serial No. 08/064,693, filed May 19, 1993, which are incorporated herein by reference in their entirety. Generally, those skilled in the art will recognize that peptides as described herein may be modified by a variety of chemical techniques to produce compounds having essentially the same activity as the unmodified peptide, and optionally having other desirable properties. For example, carboxylic acid groups of the peptide, whether carboxyl-terminal or sidechain, may be provided in the form of a salt of a pharmaceutically-acceptable cation or esterified to form a C r C 16 ester, or converted to an amide of formula NRjR 2 wherein R x and R 2 are each independently H or C r C 16 alkyl, or combined to form a heterocyclic ring, such as 5- or 6-membered. Amino groups of the peptide, whether amino-terminal or sidechain, may be in the form of a pharmaceutically-acceptable acid addition salt, such as the HCl, HBr, acetic, benzoic, toluene sulfonic, maleic, tartaric and other organic salts, or may be modified to C r C 16 alkyl or dialkyl amino or further converted to an amide. Hydroxyl groups of the peptide sidechain may be converted to -Cig alkoxy or to a Cj-C 16 ester using well-recognized techniques. Phenyl and phenolic rings of the peptide sidechain may be substituted with one or more halogen atoms, such as fluorine, chlorine, bromine or iodine, or with -C^ alkyl, C,-C 16 alkoxy, carboxylic acids and esters thereof, or amides of such carboxylic acids. Methylene groups of the peptide sidechains can be extended to homologous C 2 -C 4 alkylenes. Thiols can be protected with any one of a number of well-recognized protecting groups, such as acetamide groups. Those skilled in the art will also recognize methods for introducing cyclic structures into the peptides of this invention to select and provide conformational constraints to the structure that result in enhanced binding and/or stability. For example, a carboxyl-terminal or amino-terminal cysteine residue can be added to the peptide, so that when oxidized the peptide will contain a disulfide bond, thereby generating a cyclic peptide. Other peptide cyclizing methods include the formation of thioethers and carboxyl- and amino-terminal amides and esters. Peptidomimetic and organomimetic embodiments are also hereby explicitly declared to be within the scope of the present invention, whereby the three-dimensional arrangement of the chemical constituents of such peptido- and organomimetics mimic the three-dimensional arrangement of the peptide backbone and component amino acid sidechains in the peptide, resulting in such peptido- and organomimetics of the peptides of this invention having substantial biological activity. It is implied that a pharmacophore exists for each of the described activities of BPI. A pharmacophore is an idealized, three- dimensional definition of the structural requirements for biological activity. Peptido- and organomimetics can be designed to fit each pharmacophore with current computer modelling software (computer aided drug design). The degree of overlap between the specific activities of pharmacophores remains to be determined. The administration of BPI functional domain peptides is preferably accomplished with a pharmaceutical composition comprising a BPI functional domain peptide and a pharmaceutically acceptable diluent, adjuvant, or carrier. The BPI functional domain peptide composition may be administered without or in conjunction with known antibiotics, surfactants, or other chemotherapeutic agents. Examples of such combinations are described in co-owned, copending, U.S. Patent Application Serial No. 08/012,360, filed February 2, 1993, and continuation-in-part U.S. Patent Application Serial No. 08/190,869, filed February 2, 1994, the disclosures of which are incorporated herein by reference. Effective doses of BPI functional domain peptides for bactericidal activity, partial or complete neutralization of the anti-coagulant activity of heparin, partial or complete neutralization of LPS and other effects described herein may be readily determined by those of skill in the art according to conventional parameters, each associated with the corresponding biological activity, including, for example, the size of the subject, the extent and nature of the bacterial infection, the extent and nature of the endotoxic shock, and the quantity of heparin administered to the subject and the time since administration of the heparin. Similar determinations will be made by those of skill in this art for using the peptide embodiments of this invention for therapeutic uses envisioned and described herein. Embodiments of the invention comprising medicaments can be prepared for oral administration, for injection, or other parenteral methods and preferably include conventional pharmaceutically acceptable carriers, adjuvents and counterions as would be known to those of skill in the art. The medicaments are preferably in the form of a unit dose in solid, semi-solid and liquid dosage forms such as tablets, pills, powders, liquid solutions or suspensions, and injectable and infusible solutions. Effective dosage ranges /OO from about 100 μg/kg to about ^ lβ mg/kg of body weight are contemplated. The Examples which follow are illustrative of specific embodiments of the invention, and various uses thereof. Example 1 describes the preparation of proteolytic fragments of BPI; Example 2 describes the results of bactericidal assays of the proteolytic fragments of Example 1; Example 3 describes the results of heparin binding assays using the proteolytic fragments of Example 1; Example 4 describes the results of experiments using Limulus amebocyte lysates to assay the LPS binding activity of the proteolytic fragments of Example 1; Example 5 describes the preparation of 15-mer peptides of BPI; Example 6 describes the results of heparin binding assays using the 15-mer peptides of Example 5; Example 7 describes the results of Limulus amebocyte lysates assays using the 15-mer peptides of Example 5; Example 8 describes the results of bactericidal assays of the 15-mer peptides of Example 5; Example 9 describes the preparation of BPI individual functional domain peptides; Example 10 describes the results of heparin binding assays using the BPI individual functional domain peptides of Example 9; Example 11 describes the results of heparin neutralization assays using the BPI individual functional domain peptides of Example 9; Example 12 describes the results of Limulus amebocyte lysates assays of LPS neutralization activity using the BPI individual functional domain peptides of Example 9; Example 13 describes the results of bactericidal assays of the BPI individual functional domain peptides of Example 9; Example 14 describes the preparation of BPI combination functional domain peptides; Example 15 describes the results of bactericidal activity assays of the BPI combination functional domain peptides of Example 14; Example 16 describes the results of additional bactericidal activity assays of the BPI combination functional domain peptides of Example 14; Example 17 describes the results of in vivo and in vitro heparin neutralization assays using the BPI combination functional domain peptides of Example 14; Example 18 describes the preparation and functional activity analysis of bactericidal activity, heparin binding activity and LPS neutralization activity assays of BPI substitution variant functional domain peptides; Example 19 provides a summary of the results of bactericidal and heparin binding assays using representative BPI functional domain peptides; Example 20 describes analysis of BPI functional domain peptides in a variety of binding and neutralization assays; Example 21 addresses a heparin neutralization assay; Example 22 describes administration of BPI functional domain peptides in model systems of collagen and bacteria- induced arthritis animal model systems exemplifying treatment of chronic inflammatory disease states; Example 23 illustrates testing of BPI functional domain peptides for angiostatic effects in a mouse malignant melanoma metastasis model system; Example 24 addresses effects of BPI functional domain peptides on endothelial cell proliferation; Example 25 describes analysis of BPI functional domain peptides in animal model systems; and Example 26 describes a protocol for testing the anti-endotoxin effects of BPI functional domain peptides of the invention in vivo in humans. EXAMPLE 1 Preparation of BPI Proteolytic. Fragments Chemical cleavage and enzymatic digestion processes were applied to rBPI^ to produce variously-sized proteolytic fragments of the recombinant BPI protein. rBPI^ protein was reduced and alkylated prior to proteolysis by cyanogen bromide (CNBr) or endoproteinase Asp-N. The protein was desalted by overnight precipitation upon the addition of cold (4°C) acetone (1:1 v/v) and the precipitated protein recovered by pelleting under centrifugation (5000 x g) for 10 minutes. The rBPI^ protein pellet was washed twice with cold acetone and dried under a stream of nitrogen. An rBPI^ solution was then reconstituted to a final concentration of 1 mg protein/mL in 8M urea 0.1M Tris-HCl (pH 8.1) and reduced by addition of 3.4 mM dithiothreitol (Calbiochem, San Diego, CA) for 90 minutes at 37°C. Alkylation was performed by the addition of iodoacetamide (Sigma Chemical Co., St. Louis, MO) to a final concentration of 5.3 millimolar and incubation for 30 minutes in the dark at room temperature. The reduced and alkylated protein was acetone-precipitated, centrifuged and washed as described above and the pellet was redissolved as described below for either CNBr or Asp-N digestion. For CNBr-catalyzed protein fragmentation, the washed pellet was first dissolved in 70% trifluoroacetic acid (TFA) (Protein Sequencing Grade, Sigma Chemical Co., St. Louis, MO) to a final protein concentration of 5 mg/mL. Cyanogen bromide (Baker Analyzed Reagent, VWR Scientific, San Francisco, CA) dissolved in 70% TFA was added to give a final ratio of 2:1 CNBr to protein (w/w). This ratio resulted in an approximately 75-fold molar excess of CNBr relative to the number of methionine residues in the rBPI 23 protein. The reaction was purged with nitrogen and allowed to proceed for 24 hours in the dark at room temperature. The reaction was terminated by adding 9 volumes of distilled water, and followed by freezing (-70 °C) and lyophilization. For endoproteinase digestion, the reduced and alkylated rBP^ was solubilized at a concentration of 5.0 mg/mL in 8M urea/0.1M Tris-HCl (pH 8.1). An equal volume of 0.1M Tris-HCl (pH 8.1) was then added so that the final conditions were 2.5 mg/mL protein in 5M urea/0.1M Tris-HCl (pH 8.1). Endoproteinase Asp-N from Pseudomonas fragi (Boehringer-Mannheim, Indianapolis, IN) was added at a 1:1000 (w/w, enzyme: substrate) ratio, and digestion was allowed to proceed for 6 hours at 37°C. The reaction was terminated by addition of TFA to a final concentration of 0.1 % and the samples were then fractionated by reverse phase HPLC. The CNBr and Asp-N fragment mixtures were purified on a Zorbax Protein Plus C 3 column (4.6 x 250 mm, 300 A pore size, MACMOD Analytical Inc, Chadsford, PA). A gradient ranging from 5% acetonitrile in 0.1 % TFA to 80% acetonitrile in 0.1 % TFA was run over this column over a 2 hour elution period at a flow rate of 1.0 mL/min. Fragment elution was monitored at 220 nm using a Beckman System Gold HPLC (Beckman Scientific Instruments, San Ramon, CA). The column heating compartment was maintained at 35°C and the fractions were collected manually, frozen at -70°C and dried in a Speed Vac concentrator. Fragments were then solubilized in a solution of 20 mM sodium acetate (pH 4.0)/0.5 M NaCl prior to use. Electrospray ionization mass spectrometry (ESI-MS) was performed on a VG Bio-Q mass spectrometer by Dr. Francis Bitsch and Mr. John Kim in the laboratory of Dr. Cedric Shackleton, Children's Hospital-Oakland Research Institute. Molecular masses were obtained by mathematical transformation of the data. Although the DNA sequence for rBPI^ encodes amino acid residues 1- 199 of the mature protein, a significant portion of the protein that is produced is truncated at Leu- 193 and Val- 195, as determined by ESI-MS. The existence of these carboxyl-terminal truncations were verified by isolating the carboxyl- terminal tryptic peptides, which were sequenced and analyzed by ESI-MS. There are six methionine residues in the rBPI^ protein, at positions 56, 70, 100, 111, 170, and 196, and chemical cleavage by cyanogen bromide produced six major peptide fragments as predicted. The results of the CNBr cleavage experiments are summarized in Table I. The fragments were isolated by reverse phase (C 3 ) HPLC (Figure la) and their amino-terminal sequences were determined by Edman degradation. The two largest fragments (Cl and C5) were not resolved by the C 3 HPLC column and further attempts to resolve them by ion exchange chromatography were unsuccessful, presumably because they are similar in length and isoelectric point. The identities of the Cl, C5 fragments within the mixture were determined by ESI-MS. The predicted mass of Cl is 6269 (Table I), taking into account the loss of 30 a.m.u. resulting from the conversion of the carboxyl-terminal methionine to homoserine during the CNBr cleavage reaction. The observed mass of 6251.51 ± 0.34 is consistent with the loss of a water molecule (18 a.m.u.) in a homoserine lactone intermediate, which may be favored over the formation of the homoserine because of the hydrophobicity of the Cl fragment C-terminal amino acids. The predicted mass of the C5 fragment is 6487 and the observed mass is 6385.84 ± 0.39 (Table I). For the C5 fragment, the C-terminal amino acids are hydrophilic, so the hydrolysis of the homoserine lactone intermediate is probably favored. From both the amino-terminal sequencing and the mass spectrum data, the C5 component represents approximately 10-25% of the material in the C1/C5 mixture. Proteolytic cleavage with endoproteinase Asp-N was performed to provide additional fragments for the regions contained within the CNBr C1/C5 mixture. There are six aspartic acid residues within the rBPI^ sequence at positions 15, 36, 39, 57, 105, and 116. The six major Asp-N fragments isolated by C 3 HPLC (Figure lb) were sequenced and masses were determined by ESI-MS (Table I). A short duration digest at a 1:1000 (w/w, enzyme: substrate) ratio was used to eliminate potential non-specific cleavages, particularly at glutamic acid residues. It is evident that this digestion did not continue until completion, as one fragment (1-38) was isolated where Asp residues (amino acids 15 and 35) were not cleaved. The mass spectra of the Asp-N fragments were consistent with the predicted masses for each individual fragment. Unlike the CNBr cleavage, where the carboxyl-terminal fragment was poorly resolved, the Asp-N fragment from amino acid 116 to the carboxyl- terminus was well resolved from all of the other Asp-N fragments. TABLE I EXAMPLE 2 Bactericidal Effects of BPI Proteolvtic. Fragments BPI proteolytic fragments produced according to Example 1 were screened for bactericidal effects using rough mutant E. coli J5 bacteria in a radial diffusion assay. Specifically, an overnight culture of E. coli J5 was diluted 1:50 into fresh tryptic soy broth and incubated for 3 hours at 37°C to attain log phase growth of the culture. Bacteria were then pelleted at 3,000 rpm for 5 minutes in a Sorvall RT6000B centrifuge (Sorvall Instruments, Newton, CT). 5 mL of 10 mM sodium phosphate buffer (pH 7.4) was added and the preparation was re-pelleted. The supernatant was decanted and 5 mL of fresh buffer was added, the bacteria were resuspended and their concentration was determined by measurement of absorbance at 590 nm (an Absorbance value of 1.00 at this wavelength equals a concentration of 1.25 x 10 9 CFU/mL in suspension). The bacteria were diluted to 4 x 10 6 CFU/mL in 10 mL of molten underlayer agarose (at approximately 45 °C) and inverted repeatedly to mix in 15 mL polypropylene tubes conventionally used for this purpose. The entire contents of such tubes were then poured into a level square petri dish and distributed evenly by rocking the dish side-to-side. The agarose hardened in less than 30 seconds and had a uniform thickness of about 1 mm. A series of wells were then punched into the hardened agarose using a sterile 3 mm punch attached to a vacuum apparatus. The punch was sterilized with 100% alcohol and allowed to air dry prior to use to avoid contaminating the bacterial culture. 5 or 10 μL of each of the BPI fragments were carefully pipetted into each well. As a negative control, dilution buffer (pH 8.3) was added to a separate well, and rBPI^ at concentrations of 5 μg/mL and 1 μg/mL were also added as positive controls. Each plate was incubated at 37 °C for 3 hours, and then 10 mL of molten overlayer agarose (at approximately 45 °C) was added into the level petri dish, allowed to harden and incubated overnight at 37°C. The next day, a clear zone was seen against the lawn of bacteria in those wells having bactericidal activity. In order to visually enhance this zone, a dilute Coomassie solution (consisting of 0.002% Coomassie Brilliant Blue, 27% methanol, 15% formaldehyde (37% stock solution) and water) was poured over the agar and allowed to stain for 24 hours. The bacterial zones were measured with a micrometer. No bactericidal activity was discerned for the rBPI 23 fragments generated by CNBr or by Asp-N digestion, when tested at amounts up to 25 pmol/well. In contrast, this assay detected measurable bactericidal activity using rBPI^ in amounts as low as 0.75 pmol/well. Reduced and alkylated rBPI^, on the other hand, also was not bactericidal at amounts up to 100 pmol/well, while alkylated rBPI-y retained bactericidal activity equivalent to rBP^. EXAMPLE 3 Heparin Binding by BPI Proteolvtic Fragments rBPI^ and the BPI proteolytic fragments produced according to Example 1 were evaluated in heparin binding assays according to the methods described in Example 1 in copending U.S. Patent Application Serial No. 08/093,202, filed July 15, 1993 and incorporated by reference. Briefly, each fragment was added to wells of a 96-well microtiter plate having a polyvinylidene difluoride membrane (Immobilon-P, Millipore, Bedford, MA) disposed at the bottom of the wells. Heparin binding of CNBr fragments was estimated using 100 picomoles of each fragment per well with a saturating concentration of 3 H-heparin (20 μg/mL). Positive control wells contained varying amounts of TΕPI 23 . The wells were dried and subsequently blocked with a 0.1% bovine serum albumin (BSA) in phosphate buffered saline, pH 7.4 (blocking buffer). Dilutions of 3 H-heparin (0.03-20 tCi/ml, avg. M.W. = 15,000; DuPont-NEN, Wilmington, DE) were made in the blocking buffer and incubated in the BPI peptide-containing wells for one hour at 4°C. The unbound heparin was aspirated and the wells were washed three times with blocking buffer, dried and removed for quantitation in a liquid scintillation counter (Model 1217, LKB, Gaithersburg, MD). Although BSA in the blocking buffer did show a low affinity and capacity to bind heparin, this was considered physiologically irrelevant and the background was routinely subtracted from the test compound signal. The specificity of fragment-heparin binding was established by showing that the binding of radiolabeled heparin was completely inhibited by a 100-fold excess of unlabeled heparin (data not shown). The results, shown in Table π (as the mean values of duplicate wells + the range between the two values), indicated that the CNBr fragments containing the amino acids 71-100 (C3) and 1-56 and 112-170 (Cl,5) bound heparin to a similar extent. The CNBr fragment 171-196 also bound more heparin than the control protein (thaumatin, a protein of similar molecular weight and charge to rBPI 23 ). The Asp-N fragments also demonstrated multiple heparin binding regions in rBPI^. As seen in Table π, the 57-104 Asp-N fragment bound the highest amount of heparin, followed by the 1-38 and 116-193 fragments. These data, in combination with the CNBr fragment data, indicate that there are at least three separate heparin binding regions within rBP^, as demonstrated by chemically or enzymatically-generated fragments of rBPI^, with the highest heparin binding capacity residing within residues 71-100. EXAMPLE 4 Effect of BPI Proteolvtic Fragments on an LAL Assay BPI proteolytic fragments produced according to Example 1 were subjected to a Limulus Amoebocyte Lysate (LAL) inhibition assay to determine LPS binding properties of these fragments. Specifically, each of the fragments were mixed in Eppendorf tubes with a fixed concentration of E. coli 0113 LPS (4 ng/mL final concentration) and incubated at 37 °C for 3 hours with occasional shaking. Addition controls comprising rBP^ at 0.05 μg/mL were also tested. Following incubation, 360 μL of Dulbecco's phosphate buffered saline (D-PBS; Grand Island Biological Co. (GIBCO), Long Island, NY) were added per tube to obtain an LPS concentration of 200 pg/mL for the LAL assay. Each sample was then transferred into Immulon π strips (Dynatech, Chantilly, VA) in volumes of 50 μl per well. Limulus amoebocyte Lysate (Quantitative Chromogenic LAL kit, Whitaker Bioproducts, Inc., Walkersville, MD) was added at 50 μL per well and the wells were incubated at room temperature for 25 minutes. Chromogenic substrate was then added at a volume of 100 μL per well and was well mixed. After incubation for 20 to 30 minutes at room temperature, the reaction was stopped with addition of 100 μL of 25% (v/v) acetic acid. Optical density at 405 nm was then measured in a multiplate reader (Model Vmax, Molecular Dynamics, Menlo Park, CA) with the results shown in Figure 2 in terms of percent inhibition of LPS. In this Figure, the filled circle represents rBPI^; the open circle represents Asp-N fragment A3; the x represents Asp-N fragment A2; the filled square represents Asp-N fragment A4; the filled triangle represents Asp-N fragment A1A2; the open square represents Asp-N fragment A6a; the small open triangle represents CNBr fragment C3; and the small filled square represents CNBr fragment C1/C5. The CNBr digest fraction containing amino acid fragments 1-56 and 112-170 inhibited the LPS-induced LAL reaction with an IC 50 of approximately 100 nM. This IC 50 is approximately 10-fold higher than the IC 50 for intact TBPI_ 3 (9 nM) in the same assay. The other CNBr digest fragments were found to be non-inhibitory. A slightly different result was observed with fragments generated from the Asp-N digest, where three fragments were found to be inhibitory in the LAL assay. The fragment corresponding to amino acids 116-193 exhibited LAL inhibitory activity similar to intact rBP^ with complete inhibition of the LPS-induced LAL reaction at 15 nM. The fragments corresponding to amino acids 57-104 and 1-38 also inhibited the LAL assay, but required 10-fold higher amounts. These results, in combination with the CNBr digest results, further supported the conclusion from previously-described experimental results that at least three regions of the rBPI^ molecule have the ability to neutralize LBS activation of the LAL reaction, with the most potent region appearing to exist within the 116-193 amino acid fragment. Immunoreactivity studies of the proteolytic fragments of rBP^ described in Example 1 were performed using ELISA assays. In such assays, a rabbit polyclonal anti-rBPI^ antibody, capable of blocking rBPI^ bactericidal and LAL inhibition properties, and two different, non-blocking mouse anti-rBPI 23 monoclonal antibodies were used to probe the rBPI^ proteolytic fragments. The polyclonal antibody was found to be immunoreactive with the 116-193 and 57-104 Asp-N fragments and with the 1-56 and 112-170 CNBr fragments, while the murine monoclonal antibodies reacted only with an Asp-N fragment representing residues 1-14 of rBPI^. EXAMPLE 5 Preparation of 15-mer Peptides of BPI In order to further assess the domains of biological activity detected in the BPI fragment assays described in Examples 1-4, 15-mer synthetic peptides comprised of 15 amino acids derived from the amino acid sequence of the 23kD amino terminal fragment of BPI were prepared and evaluated for heparin- binding activity, activity in a Limulus Amoebocyte Lysate Inhibition (LAL) assay and bactericidal activity. Specifically, a series of 47 synthetic peptides were prepared, in duplicate, each comprising 15 amino acids and synthesized so that each peptide shared overlapping amino acid sequence with the adjacent peptides of the series by 11 amino acids, based on the sequence of rBPI^ as previously described in copending U.S. Patent Application Serial No. 08/093,202, filed July 15, 1993. Peptides were simultaneously synthesized according to the methods of Maeji et al. (1990, Immunol. Methods 134: 23-33) and Gammon et a (1991, J. Exp. Med. 173: 609-617), utilizing the solid-phase technology of Cambridge Research Biochemicals Ltd. under license of Coselco Mimotopes Pty. Ltd. Briefly, the sequence of rBPI^ (1-199) was divided into 47 different 15-mer peptides that progressed along the linear sequence of rBP^ by initiating a subsequent peptide every fifth amino acid. This peptide synthesis technology allows for the simultaneous small scale synthesis of multiple peptides on separate pins in a 96- well plate format. Thus, 94 individual pins were utilized for this synthesis and the remaining two pins (B,B) were subjected to the same steps as the other pins without the addition of activated FMOC-amino acids. Final cleavage of the 15-mer peptides from the solid-phase pin support employed an aqueous basic buffer (sodium carbonate, pH 8.3). The unique linkage to the pin undergoes a quantitative diketopiperazine cyclization under these conditions resulting in a cleaved peptide with a cyclo(lysylprolyl) moiety on the carboxyl-terminus of each peptide. The amino-termini were not acetylated so that the free amino group could potentially contribute to anion binding reactions. An average of about 15 μg of each 15-mer peptide was recovered per well. EXAMPLE 6 Heparin Binding hy 15-mer Peptides of BPI The BPI 15-mer peptides described in Example 5 were subjected to a heparin binding assay according to the methods described in Example 3. The results of these experiments are shown in Figure 3, expressed as the total number of cpm bound minus the cpm bound by control wells which received blocking buffer only. These results indicated the existence of three distinct subsets of heparin-binding peptides representing separate heparin-binding functional domains in the rBPI 23 sequence. In the BPI sequence, the first domain was found to extend from about amino acid 21 to about amino acid 55; the second domain was found to extend from about amino acid 65 to about amino acid 107; and the third domain was found to extend from about amino acid 137 to about amino acid 171. Material from the blank control pins showed no heparin binding effects. EXAMPLE 7 Effect of 15-mer Peptides of BPI on an IAmulus Amnebocyte Lysate (LAP Assay The 15-mer peptides described in Example 5 were assayed for LPS binding activity using the LAL assay described in Example 4. The results of these experiments are shown in Figure 4. The data in Figure 4 indicated at least three major subsets of peptides representing three distinct domains of the rBPI-y protein having LPS-binding activity resulting in significant LAL inhibition. The first domain was found to extend from about amino acid 17 to about amino acid 55; the second domain was found to extend from about amino acid 73 to about amino acid 99; and the third domain was found to extend from about amino acid 137 to about amino acid 163. In addition, other individual peptides also exhibited LAL inhibition, as shown in the Figure. In contrast, material from blank control pins did not exhibit any LPS neutralizing effects as measured by the LAL assay. EXAMPLE 8 Bactericidal Effects of 15-mer Peptides of BPI The 15-mer peptides described in Example 5 were tested for bactericidal effects against the rough mutant strain of E. coli bacteria (J5) in a radial diffusion assay as described in Example 2. Products from the blank pins (B, B) were tested as negative controls. The results of the assay are shown in Figure 5. The only 15-mer peptide found to have bactericidal activity was a peptide corresponding to amino acids 85-99 of the BPI protein. As is seen in Figure 5, the positive control wells having varying amounts of rBPI 23 also showed bactericidal activity, while the buffer and blank pin controls did not. The results of these bactericidal assays, along with the heparin binding and LAL assays described in the above Examples, indicate that there exist discrete functional domains in the BPI protein. The results shown in Examples 1-8 above indicate that rBPI 23 contains at least three functional domains that contribute to the total biological activity of the molecule. The first domain appears in the sequence of amino acids between about 17 and 45 and is destroyed by Asp-N cleavage at residue 38. This domain is moderately active in both the inhibition of LPS-induced LAL activity and heparin binding assays. The second functional domain appears in the region of amino acids between about 65 and 99 and its inhibition of LPS- induced LAL activity is diminished by CNBr cleavage at residue 70. This domain also exhibits the highest heparin binding capacity and contains the bactericidal peptide, 85-99. The third functional domain, between about amino acids 142 and 169, is active in the inhibition of LPS-induced LAL stimulation assay and exhibits the lowest heparin binding capacity of the three regions. EXAMPLE 9 Preparation of BPI Individual Functional Domain Peptides Based on the results of testing the series of overlapping peptides described in Examples 5 through 8, BPI functional domain peptides from each of the functionally-defined domains of the BPI protein were prepared by solid phase peptide synthesis according to the methods of Merrifield, 1963, J. Am. Chem. Soc. 85: 2149 and Merrifield et ah, 1966, Anal. Chem. 38: 1905-1914 using an Applied Biosystems, Inc. Model 432 peptide synthesizer. BPI functional domain peptides were prepared having the amino acid sequences of portions of amino acid residues 1-199 of BPI as set out in Table HI below and designated BPI.2 through BPI.5 and BPI.8. EXAMPLE 10 Heparin Binding Activity by BPI Individual Functional Domain Peptides BPI individual functional domain peptides BPI.2, BPI.3, and BPI.8, along with rBPI 21 Δcys were assayed for heparin binding activity according to the methods described in Example 3. The results are shown in Figure 6 and indicate that BPI.3 and rBPI 2 ιΔcys had moderate heparin binding activity and BPI.2 and BPI.8 had little or no heparin binding activity. EXAMPLE 11 Heparin Neutralization Activity of BPI Individual Functional Domain Peptides BPI functional domain peptides BPI.2, BPI.3, BPI.4, BPI.5, BPI.6, and BPI.8, along with rBPI^ as a positive control, were assayed for their effect on thrombin inactivation by ATlll/heparin complexes according to the method of Example 3 in copending and co-assigned U.S. Patent Application Serial No. 08/093,202, filed July 15, 1993, incorporated by reference. Specifically, a Chromostrate™ anti-thrombin assay kit (Organon Teknika Corp., Durham, NC) was used to examine the inhibition of purified thrombin by preformed ATiπ/heparin complexes in plasma. Briefly, the assay was performed in 96 well microtiter plates in triplicate with a final volume per well of 200 μL. Varying concentrations of the BPI functional domain peptides ranging from 1.0 μg/mL to 100 μg/mL were assayed to determine their effect on thrombin inhibition in the presence of pre-formed ATJLil/heparin complexes. The order of addition of assay components was as follows: 1) a dilution series of rBPI^ or BPI functional domain peptides or thaumatin as a control protein, with final concentrations of 100, 50, 25, 10 and 1 μg/well, diluted in PBS in a final volume of 50 μL; 2) 50 μL plasma diluted 1:100 in a buffer supplied by the manufacturer; 3) 50 μl thrombin at 1 nKat/mL in a buffer supplied by the manufacturer; and 4) 50 μL chromogenic substrate at a concentration of 1/tmol/mL in water. The reaction was allowed to proceed for 10 minutes at 37°C and stopped with the addition of 50 μL 0.1M citric acid. The colorimetric reaction was quantitated on a microplate reader as described in Example 3. The results of these assays are shown in Figures 7a and 7b, which depict the sample concentrations as weight or molar concentrations respectively. BPI functional domain peptides BPI.3 and BPI.5 each had the most significant heparin neutralization effects. In these assays, the control protein, thaumatin, showed no neutralizing effect and was essentially equivalent to the buffer control at all protein concentrations. EXAMPLE 12 LPS Neutralization Activity by LAL Assay of BPI Individual Functional Domain Peptides BPI functional domain peptides BPI.2, BPI.3, and BPI.8, along with rBPI 23 as a positive control, were evaluated in the LAL assay according to the method of Example 4 herein to determine LPS binding and inhibition properties of these peptides. The experiments were performed essentially as described in Example 3 and the results are shown in Figures 8a and 8b, which depict the sample concentrations as weight or molar concentrations respectively. The results showed that BPI.3 had moderate LPS inhibition activity and that BPI.2 and BPI.8 had no significant LPS inhibition activity. EXAMPLE 13 Bactericidal Activity Assay of BPI Individual Functional Domain Peptides BPI functional domain peptides BPI.2, BPI.3, and BPI.8, along with rBPIjs as a positive control, were tested for bactericidal effects against E. coli J5 (rough) and E. coli 0111:B4 (smooth) bacteria in a radial diffusion assay according to the methods of Example 2. The results of these assays are depicted in Figures 9a-9d. These results demonstrated that each of the BPI functional domain peptides BPI.2 and BPI.3 exhibited bactericidal activity while BPI.8 had little to no bactericidal activity. Each of the bactericidal peptides showing bactericidal activity tended to be more effective against the rough than the smooth E. coli strain. In additional experiments, broth antibacterial assays were conducted to further determine the bactericidal activity of certain of the BPI peptides. Specifically, either E. coli J5 (rough) or E. coli 0111:B4 (smooth) bacteria were selected from single colonies on agar plates and used to inoculate 5 mL of Mueller Hinton broth and incubated overnight at 37°C with shaking. The overnight culture was diluted (~ 1:50) into 5 mL fresh broth and incubated at 37°C to log phase (~ 3 hours). Bacteria were pelleted for 5 minutes at 3000 rpm (1500 x g). Bacterial pellets were resuspended in 5 mL PBS and diluted to 2 x 10 6 cells/mL in the Mueller Hinton broth (wherein 1 OD 570 unit equals 1.25 x 10 9 CFU/mL). The BPI functional domain peptides to be tested were diluted to 200 μg/mL in broth and serially diluted 2-fold in 96 well culture plates (100 μL volume). All items were at 2-fold final concentration and experiments were conducted in triplicate. Bacteria were added at 100 μL/well and the plates were incubated on a shaker at 37°C for a 20 hour period. The plates were then read on an ELISA plate multiple reader at 590 nm. One of the triplicate wells from each peptide concentration was selected for colony forming unit (CFU) determination. A 30 μL aliquot was added to 270 μL of PBS and further ten-fold serial dilutions were performed. Then a 50 μL aliquot was plated on tryptic soy agar and incubated overnight. Colonies were counted and final bacterial concentrations determined. The results of these assays are depicted in Figures 9e (for E. coli 15) and 9f (for E. coli 0111:B4). As shown in these Figures, BPI functional domain peptide BPI.3 had significant anti-bacterial activity against E. coli J5 bacteria and less activity against E. coli 0111:B4 bacteria. EXAMPLE 14 Preparation of BPI Combination Functional Domain Peptides Combination peptides were prepared using solid-phase chemistry as described in Example 9. The sequences of these peptides are shown in Table IV. It will be noted that the peptides designated BPI.7, BPI.9 and BPI.10 represent partial or even multiple repeats of certain BPI sequences. Specifically, BPI.7 comprises a 20-mer consisting of amino acid residues 90-99 repeated twice in a single linear peptide chain. BPI.10 comprises an approximately 50:50 admixture of a 25-mer (designated BPI.10.1; SEQ ID NO:55) and a 26-mer (designated BPI.10.2; SEQ ID NO:65) consisting of amino acid residues 94-99, 90-99, 90-99 and 93-99, 90-99, 90-99, respectively, in a single linear peptide chain. BPI.9 comprises a 16-mer comprising amino acid residues 94-99 followed by residues 90-99 in a single linear peptide chain. These peptides were used in each of the BPI activity assays described in Examples 10-13 above. In the heparin binding assay described in Example 10 and shown in Figure 6, BPI.7 had extremely high heparin binding capacity. In the heparin neutralization assay described in Example 11 and shown in Figures 7a and 7b, BPI.7 had significant heparin neutralization effects compared with rBPI^. In the LAL assay described in Example 12 and shown in Figures 8a and 8b, BPI.7 had significant LPS inhibition properties. In bactericidal assays using radial diffusion plates as described in Example 13 and shown in Figures 9a-9d, each of the BPI functional domain peptides BPI.7, BPI.9 and BPI.10.1 and BPI.10.2 exhibited bactericidal activity, and significant bactericidal activity was also found for BPI.7, BPI.9 and BPI.10.1 and BPI.10.2 against both rough and smooth variant strains of E.coli in broth assays. The BPI.10 peptides exhibited the highest bactericidal activity observed against either bacterial strain. These bactericidal activity results obtained with peptides BPI.7 and BPI.10 showed that a linear dimer (BPI.7) and a mixture of linear multimers (BPI.10.1 and BPI.10.2) of the BPI domain H peptide KWKAQKRFLK (i.e. , BPI.8, SEQ ID NO:8) had bactericidal activity against E. coli strain J5, and that the monomer (BPI.8) showed essentially no bactericidal activity. Moreover, both the dimer and the multimer peptides had higher bactericidal activity that of BPI.9, comprising amino acids 94-99, 90-99. On the basis of these results, the additional peptides shown in Table IV were synthesized using the methods described in Example 9. EXAMPLE 15 Bactericidal Activity of Combination Functional Domain Peptides The BPI combination functional domain peptides described in Example 14 were used in radial diffusion bactericidal assays essentially as described in Examples 2 and 13 above. These results are shown in Figures lOa-lOe. The results shown in Figure 10a demonstrate that BPI.8, comprising one copy of a domain π peptide (amino acids 90-99), had no detectable bactericidal activity against E. coli J5 cells at concentrations of 1000 μg/mL. In contrast, BPI.13, comprising one copy of a domain IH monomer (amino acids 148-161) showed appreciable bactericidal activity at concentrations greater than 30 μg/mL. BPI.29, comprising two copies of a domain IQ monomer BPI.13, had greater bactericidal activity, and BPI.30, comprising a linear combination of the domain II peptide BPI.8 and the domain IU peptide BPI.13, showed the highest bactericidal activity against J5 cells, approximating that of BPI. Figure 10b shows the results of experiments with domain II peptides comprising BPI.8, BPI.7 and BPI.10. (See also summary Table Vm.) Although BPI.8 showed no bactericidal activity against E. coli J5 cells at concentrations of 1000 μg/mL, the combination peptides BPI.7 and BPI.10 showed high levels of bactericidal activity. Additional experiments were performed using various other bacteria as target cells to examine the range of bactericidal killing of these BPI functional domain peptides. Figure 10c shows the results of radial diffusion experiments using E. coli strain O7-K1. In these experiments, rBPI^ showed no bactericidal activity at concentrations of 100 μg/mL, and low bactericidal activity even at concentrations of 1000 μg/mL. Similarly low levels of bactericidal activity were found with the peptides BPI.8 comprising the domain π (DII) monomer and BPI.13 comprising the domain HI (DID) monomer, although the amount of activity of BPI.13 was found to be higher than that of rBPI^. Surprisingly, the domain II dimer BPI.7 and the domain Il-domain IH (DΠ-DIII) heterodimer BPI.30 showed high levels of bactericidal activity, and the domain III dimer BPI.29 showed moderate bactericidal activity. These results demonstrated that peptides of the functional BPI functional domain identified herein possess bactericidal activity qualitatively different from the bactericidal activity of the BPI molecule itself. Figures lOd and lOe show results that further demonstrate that the homo- and heterodimers described herein have qualitatively and quantitatively different bactericidal activity spectra of susceptible bacteria. Figure lOd shows the results of radial diffusion assays using Klebsiella pneumoniae bacteria. The DΠ-DIQ heterodimer BPI.30 showed the highest amount of bactericidal activity against this bacteria, the Din homodimer BPI.29 showed moderate levels of activity, and the DU dimer (BPI.7) and Dm monomer (BPI.13) showed low levels of activity. BPI.8, comprising the DU monomer, showed no bactericidal activity at concentrations of 800 μg/mL, consistent with the lack of bactericidal activity of this peptide seen with the E. coli strains tested. Figure lOe shows the levels of bactericidal activity found in radial diffusion experiments using the Gram-positive bacterium Staphylococcus aureus. The DII-Diπ heterodimer BPI.30 showed the highest amount of bactericidal activity against this bacteria, the Din homodimer BPI.29 showed moderate levels of activity, and DU dimer (BPI.7) and the Dm monomer (BPI.13) showed low levels of activity. BPI.8, comprising the DH monomer, showed no bactericidal activity at concentrations of 800 μg/mL, consistent with the lack of bactericidal activity of this peptide seen with the other bacteria. These results showed that the homo- and heterodimers disclosed herein possessed varying amounts of bactericidal activity, which varied both with regard to the amount of such activity and the minimum effective concentration of the peptide necessary for bactericidal activity to be detected. These results also showed that these peptides possessed quantitatively and, more surprisingly, qualitatively different bactericidal activity than the BPI itself. EXAMPLE 16 Additional Bactericidal Activity of BPI Combination Functional Domain Peptides In light of the results of the experiments disclosed in Example 15, the bactericidal activity of domain π-domain combination peptides ' were compared with the bactericidal activity of each of the component BPI domain II and domain HI peptides, against a number of different bacteria and other microorganisms. The following BPI functional domain peptides as described above were used in radial diffusion bactericidal assays (Example 2) and broth bactericidal assays (Example 13) essentially as described in Example 15 above. These results are shown in Figures lla-llq. These Figures show results of bactericidal assays using the following bacterial strains: Gram-negative bacteria BPI peptides tested Pseudomonas aeruginosa BPI.8, BPI.13, BPI.30 E. coli O18:Kl:H7 BPI.8, BPI.13, BPI.30 Klebsiella pneumoniae BPI.8, BPI.13, BPI.30 E. coli 075 BPI.8, BPI.13, BPI.30 Serra a marcescens BPI.8, BPI.13, BPI.30 Proteus mirabilis BPI.2, BPI.13, BPI.30 Salmonella typhurium BPI.23, BPI.30 E. coli O86a:K61 BPI.23, BPI.30 E. coli 04:K12 BPI.30 Gram-positive bacteria Streptococcus pneumonia BPI.29, BPI.30., BPI.48, BPI.55, BPI.13, BPI.69 Bacillus megaterium BPI.2, BPI.7, BPI.45, BPI.46, BPI.47, BPI.48 Staphylococcus aureus BPI.7, BPI.8, BPI.10, BPI.13, BPI.30 Fungi Candida albicans BPI.30, BPI.13, BPI.29, BPI.48, BPI.2 The results of these experiments are summarized as follows. None of the BPI peptides tested showed any bactericidal activity against S. marcescens (Figure llf) or P. mirabilis (Figure llg). BPI.8 showed no bactericidal activity against any organism tested at concentrations up to about 2000 pmol. BPI.13 and BPI.30 showed bactericidal activity against P. aeruginosa (Figure 11a), E. coli O18:Kl:H7 (Figure lib), K. pneumoniae (Figure lie), and E. coli 075 (Figure lid). Additionally, BPI.30 showed bactericidal .activity against S. typhurium (Figure llh), and, in broth assays, E. coli O86a:K51 (Figure llj) and E. coli O4:K12 (Figure Ilk). BPI.23 showed bactericidal activity in a radial diffusion assay against E. coli O86a:K61 (Figure Hi). Additionally, BPI.30 showed bactericidal activity against E. coli O86a:K61 in human serum (Figure 111). The bactericidal capacity of BPI peptides provided by the invention was also tested against Gram-positive bacteria. Surprisingly, every BPI peptide tested showed some bactericidal activity in radial diffusion assays using 5. aureus (Figure He), S. pneumoniae (Figure 11m) and B. megaterium (Figure lln) at amounts ranging between about 20 and about 2000 pmol. These results compared favorably with bactericidal activity of the antibiotics gentamicin and vancomycin (Figure Ho). Most surprisingly, one peptide, BPI.13, was found to have fungicidal activity in a broth assay using C. albicans (Figures lip and llq). As shown in these Figures, the activity of BPI.13 is clearly distinguishable from the much lower activity levels of BPI.2, BPI.29, BPI.30, and BPI.48. These results demonstrate that the BPI functional domain peptides of the invention have antimicrobial activity qualitatively distinct from the activity previously reported for native BPI. EXAMPLE 17 Heparin Neutralization Activity of BPI Combination Functional Domain Peptides The in vitro and in vivo heparin neutralization capacity of the BPI combination functional domain peptides prepared in Example 14 was determined by assaying the ability of these peptides to counteract the inhibitory effect of heparin on clotting time of heparinized blood and plasma. In vitro, the effect of BPI combination functional domain peptides was determined on heparin-mediated lengthening of activated partial thrombin time (APTT). The APTT is lengthened by the presence of endogenous or exogenous inhibitors of thrombin formation, such as therapeutically administered heparin. Thus, agents which neutralize the anti-coagulant effects of heparin will reduce the APTT measured by the test. Citrated human plasma (200 μL) was incubated for 1 minute at 37°C with either 15 μL of diluent (0.15 M NaCl, 0.1 M Tris-HCl, pH 7.4) or 15 μL of the diluent also containing 25 μg/mL heparin (187 units/mg). Various concentrations (from 0.0 to 56 μg/mL) of ΓBPI^, rBPI 21 Δcys, or BPI combination peptides BPI.29 (the Dili homodimer) and BPI.30 (heterodimer DE + Dili) in a volume of 15 μL were added, followed immediately by 100 μL of thrombin reagent (Catalog No. 845- 4, Sigma Chemical Co., St. Louis, MO). Clotting time (thrombin time) was measured using a BBL Fibrometer (Becton Dickenson Microbiology Systems, Cockeysville, MD). The results are shown in Figures 12a, 12b and 12e. Figure 12a shows the relative decrease caused by addition of varying amounts of rBPI 23 or rBPI 21 Δcys to the heparin-prolonged APTT. These results establish that each of these BPI-related proteins inhibits the heparin-mediated lengthening of APTT. Figure 12b shows that the BPI combination peptides BPI.29 and BPI.30 also inhibit the heparin-mediated lengthening of APTT. Figure 12e illustrates the results obtained with BPI.30 on a non-log scale. Figure 12g shows that BPI.29, BPI.30, and BPI.7 have the greatest effect on the clotting time of heparinized blood in the assay. BPI.3 and rBPI 23 show a smaller effect, and BPI.14, BPI.2, BPI.4, BPI.5, BPI.7, and rLBP^, rBPI and rBPI 21 Δcys all show less of a decrease in clotting times of heparinized blood in this assay. The in vivo effect of exemplary BPI combination peptides on APTT in heparinized rats was determined and compared with the in vivo effect of rBPI 23 . APTT is lengthened by the presence of endogenous or exogenous inhibitors of thrombin formation, such as therapeutically administered heparin. Agents which neutralize the anti-coagulant effects of heparin will reduce the APTT as measured by this test. Sprague-Dawley rats housed under NIH guidelines were administered with 100 U/kg heparin by bolus intravenous injections via the animals' tail vein followed 5 minutes later by administration of varying amounts of test or control protein as compared with rBPI 23 . The APTT was then determined from blood samples collected from the abdominal aorta 2 minutes after the administration of the test or control protein. The APTT of untreated animals, as well as animals treated only with a BPI peptide, was also determined. Figure 12c shows the dose dependence of rBPI 23 inhibition of heparin-mediated lengthening of partial thromboplastin time, and that administration of about 5mg/kg results in a APTT of the heparinized and BPI- treated animals that is almost the same as the untreated control animals. The results of similar experiments shown in Figure 12d demonstrate that the unrelated protein thaumatin has no effect on APTT times in heparinized animals. The administration of BPI.10 peptide results in a APTT in heparinized animals that is essentially the same as the APTT in control animals treated with BPI.10 alone. Similar results using BPI.30 were also obtained (Figure 12f). These results show that BPI functional domain combination peptides (e.g. , BPI.10 and BPI.30) and rBP^ effectively neutralize heparin inhibition of coagulation proteases. Based on these characteristics, BPI combination functional domain peptides of the invention are projected to be useful in the clinical neutralization of heparin anti-coagulant effects in dosages generally corresponding functionally to those recommended for protamine sulfate, but are not expected to possess the severe hypotensive and anaphylactoid effects of that material. EXAMPLE 18 Preparation and Functional Activity Analysis of BPI Substitution Variant Functional Domain Peptides The results obtained above with peptides from functional domains II and ffl prompted a further effort to determine the functionally-important amino acid residues within these peptides. Accordingly, a series of peptides comprising the amino acid sequences of domains II and III were prepared in which one of the amino acids in the sequence was substituted with an alanine residue. Diagrams of the domain peptides used in the substitution experiments are shown in Figure 13 (domain II; IKISGKWKAQKRFLK, SEQ ID No.:7) and Figure 14 (domain IH; KSKVGWLIQLFHKK, SEQ ID No.: 13). These peptide series were then tested for heparin binding affinity (Kj), heparin binding capacity (Hep-CAP), LPS neutralization as determined using the Limulus Ameboctye Lysate assay (LAL), and bactericidal activity against E.coli J5 using the radial diffusion assay (RAD), each assay as performed as described in the Examples above. The results, shown in Table V (domain π) and Table VI (domain m), are expressed in terms of the fold difference in activity in each of these assays (except for the LAL assay where relative differences are noted) between the BPI functional domain π and domain m peptides and each alanine substituted variant peptide thereof. For domain II peptides, most alanine-substituted peptides showed an approximately 2- to 10-fold reduction in bactericidal activity in the radial diffusion assay. Exceptions to this overall pattern include BPI.19 (Gly 89 → Ala 89 ), BPI.22 and BPI.24 (Lys 95 → Ala^). In contrast, most alanine-substituted peptides showed no difference in the LAL assay; BPI.17 (Iteg, → Ala 87 ) and BPI.21 (Trp 9 ι → Ala^) showed a moderate and large decrease in activity, respectively, in this assay. For BPI.21, these results were consistent with the more than 10-fold reduction in bactericidal activity found for this peptide, indicating that amino acid 91 (a tryptophan residue in the native sequence) may be particularly important in conferring biological activity on the peptide. The effect of alanine substitution on heparin binding and capacity was, in almost all cases, no more than 2-fold more or less than the unsubstituted peptide. One exception was the heparin binding capacity of BPI.21, which was 4-fold lower than the unsubstituted peptide. This further supports the earlier results on the particular sensitivity of the various activities of these peptides to substitution at Trp 9 j. In most cases, the effect on both the K,, of heparin binding and heparin binding capacity was consistent and of about the same magnitude. In some instances, the heparin binding capacity of the substituted peptide decreased, although the K d increased slightly (BPI.18; Ser 88 → Ala 88 ), or decreased slightly (BPI.24). There were also instances where capacity was unchanged even though the K d increased (BPI.20; Lys 90 → Ala 9 o ) or decreased (BPI.19). In one instance the affinity remained unaffected and the capacity decreased almost 2-fold (BPI.25; Arg^ → Ala^). These results indicated the existence of at least one critical residue in the domain II sequence (Trp 91 ), and that the activities of the domain π peptides were for the most part only minimally affected by alanine substitution of the other domain π amino acid residues. For domain III peptides, most alanine-substituted peptides showed an approximately 2- to 5-fold reduction in bactericidal activity in the radial diffusion assay. Exceptions to this overall pattern include BPI.35 (Gly 152 → Alaι 52 ), BPI.39 (Gln 156 → Ala 156 ), BPI.42 (Hisι 59 → Ala 159 ) and BPI.44 (Lys 16ι → Ala 161 ). Most alanine-substituted peptides showed no difference in the LAL assay; BPI.31 (Lys 14g → Ala 148 ), BPI.32 (Ser 149 → Ala 149 ), BPI.33 (Lys 150 → Ala 1S o), and BPI.34 (Val 151 → Ala 151 ) showed a moderate decrease in LPS- binding activity, and BPI.36 (Trp 153 → Ala 153 ) and BPI.40 (Leuι 57 → Ala 157 ) showed a large decrease in LPS-binding activity in this assay. For both BPI.36 and BPI.40, these results were consistent with the approximately 5-fold reduction in bactericidal activity found for these peptides, indicating that the hydrophobic amino acids Trp 153 and Leu 157 in the native sequence may be particularly important in conferring biological activity on the peptide. Effects of alanine substitution on heparin binding and capacity were of similar magnitude, being no more than about 5-fold more or less than the unsubstituted peptide. In almost every case, the type of effect of alanine substitutions on both the __£ < , of heparin binding and heparin binding capacity was consistent and of about the same magnitude, unlike the findings with the domain II alanine substitution peptides. In one instance (BPI.42; His 159 → Ala 159 ), the heparin binding capacity was unaffected although the K d declined slightly (1.2-fold). In only one instance was the K,, of heparin binding and heparin capacity increased slightly (BPI.35; Gly 152 → Ala 153 ); an increase of only 10% was found. Like the results found with the domain π alanine-substitution peptides, these results indicated the existence of at least one critical residue in the domain III sequence (Trp 153 ), and possibly at least one other (Leu 157 ). The results also showed that, unlike the domain II alanine-substituted peptides, almost one-half of the substitutions resulted in at least a 2-fold difference in the activities tested. In 6 cases, all four of the tested activities decreased, and in 10 instances bactericidal activity, the K,j of heparin binding and heparin capacity decreased. In only one instance (BPI.35, Gly 152 → Ala 152 ) was the activity in the bactericidal, heparin binding K d and heparin capacity assays found to have increased, albeit slightly. These results indicate that alanine replacement of the hydrophobic amino acid residues Trp 9 ι, Trp 153 and Leu 157 have the greatest effect on the activities of these BPI functional domain substitution peptides. This result is unexpected in light of the cationic nature of rBPIy. In fact, domain π alanine substitution peptides in which lysine is replaced either by alanine or phenylalanine showed dramatic increases in activity (e.g. , BPI.24, BPI.73). TABLE V BPI DOMAIN II ALANINE SUBSTITUTION PEPTIDES FOLD CHANGE IN ACTIVITY 10 15 20 TABLE VI BPI DOMAIN III ALANINE SUBSTITUTION PEPTIDES FOLD REDUCTION IN ACTIVITY BPI.13 K S KV GWL IQ L F H K K BPI.31 BPI.32 BPI.33 10 BPI.34 BPI.35 BPI.36 BPI.37 BPI.38 15 BPI.39 BPI.40 BPI.41 BPI.42 BPI.43 20 BPI.44 EXAMPLE 19 Summary of Biological Activity of BPI Functional Domain Peptides The distribution of the peptides into construct categories is presented in Table VII below. The BPI functional domain peptides of this invention, or representative subsets thereof, have been assayed for the following biological activities: bactericidal activity against Gram-negative and Gram-positive bacteria, and against certain other microorganisms; LPS binding and neutralization activities; and heparin binding and heparin neutralization activities. BPI functional domain peptides were assayed for bactericidal activity on E. coli J5 bacteria and for heparin binding as described in Examples 8 and 6, respectively. The assay results for exemplary peptides of the present invention are summarized in Table Vϋl for the Gram-negative bacteria E. coli J5 (rough) and E. coli 0113 (smooth) and the Gram-positive bacteria S. aureus. The bactericidal activities are expressed as the amount of peptide (pmol/well and μg/well) required to generate a 30 mm 2 bactericidal zone. TABLE VH Seq BPI ID Peptide Peptide No. Sequence I. BPI individual functional domain peptides Domain I Peptides QQGTAALQKELKRIK 10 LQKELKRIKIPDYSDSFKIKHL GTAALQKELKRIKIPDYSDSFKIKHLGKGH GTAALQKELKRIKIP 15 παSGKWKAQKRFLK NVGD^SISNANΠQSGKWKAQKRFL KWKAQKRFLK 20 VHVfflSKSKVGWLIQLFHKKIE KSKVWLIQLFHKK SVHVHISKSKVGWLIQLFHKKIESALRNK KSKVGWLIQLFHKK 25 GWLIQLFHKKIESALRNKMNS KWKAQKRFLKKWKAQKRFLK 30 KRFLKKWKAQKRFLK KRFLKKWKAQKRFLKKWKAQKRFLK QK FI KKWKAQKRFLKKΛVKAQKRFLK /3-Ala-Nα,Ne-[Λfa,Ne(BPI.2)Lys]Lys TABLE VH (cont'd.) Seq BPI ID Peptide Peptide No. Sequence II. Linear and branched-chain combination peptides (cont'd.) Domain πι Peptides 10 BPI.29 56 KSKVGWLIQLFHKKKSKVGWLIQLFHKK MAP.2 β-Ma-Na,Ne-[Nct,Ne(EPl.13)Lys]Lys HI. Single amino acid substitution peptides 15 20 25 30 10 15 20 25 30 10 15 BPI.100 94 KSKVKWLKLFHKK Va. Double amino add substitution/combination peptides 20 KWKAAARFLKKWKAQKRFLK KWKAQKRFLKKWKAAARFLK KWKAAARF KKWKAAARFLK Vb. Multiple amino acid substitution/combination peptides Domain II 25 Peptides BPI.69 60 KWKAAAl^LKKWKAAARFLKK VKAAARFLK BPI.99 93 K\\T AQ\\TlFIJσ \ΛT AQWW<X_KKWKAQWi T_K BPI.101 95 KSKVKWLIK FFKFKSKVKWL1KLFF F Via. Atypical amino acid substitution peptides 30 Domain II Peptides BPI.66 49 IKISGKW D KAQKRFLK BPI.67 50 IKISGKAg. (1 . MIJhthyl) KAQKRFLK BPI.70 63 IKISGKWKA β . (3 . EyΛiyl) QKRFI_K 35 TABLE Vπ (cont'd.) Peptide Sequence A D A D IKISGKWKAQKRFLK 10 IKISGKWKAQKRA β . (3 . pyridyl) nαSGKWKAQF D RFLK IKISGKWKAQA,/3-(l-naphthyl) ,R' FLK 15 BPI.83 77 KSKVGA /,3-(l-_uphfl-yl) LIQLFHKK VIb. Atypical amino acid double substitution peptides Domain II Peptides BPI.84 78 HCISGKA 'ø-(--l--pl-thyl) K- AQFRFLK 20 BPI.89 84 παSGKA^ (1 . n , phflιyl) KAFKRFLK VIc. Atypical amino acid triple substitution peptides 25 30 TABLE π (cont'd.) Seq BPI ID Peptide Peptide No. Sequence Vπ. Cyclized peptides Domain II Peptides BPI.65 10 CIKISGKWKAQKRFLKC 10 reduced Villa. Interdomain combination pepiides Domain II- Domain III Peptides 15 BPI.30 52 KWKAQKRFLKKSKVGWLIQLFHKK BPI.63 53 KISGKWKAQKRFLKKSKVGWLIQLFHKK BPI.74 70 KSKVGWLIQLFHKKKWKAQKRFLK VIHb. Interdomain combination multiple substitution peptides Domain II- 20 Domai iπ Peptides BPI.102 96 KWKAQFRFLKKSKVGW IL FHKK Vine. Atypical amino acid double substitution/interdomain combination peptides 25 Domain II- Domain UI Peptides BPI.93 88 IKISGKA wl^phw KAQFRFLKKSKVGWLIQLFHKK BPI.98 83 IKISGKA^^ ^ ^ h ^KAQFRFLKKSKVGWLIF FHKK 30 TABLE Vπi Bactericidal Activity 8 O - l 10 15 20 TABLE m Bactericidal Activity 8 o 10 TABLE m Bactericidal Activity 8 O 10 TABLE Vm Bactericidal Activity 8 10 TABLE Vm Bactericidal Activity 8 10 TABLE VIII Bactericidal Activity 8 ts. 10 TABLE Vm Bactericidal Activity 8 10 TABLE VUI Bactericidal Activity 8 10 TABLE m Bactericidal Activity 8 BPI E. coli λ5 E. coli Olll;B4 5. aureus Peptide (pmol/well) (μg/well) (pmol/well) (μg/well) (pmol/well) μg/well) > 2048.5 > 5 > 1626.1 > 5 > 1064.1 > 5 > 1329.3 > 5 > 647.5 > 5 10 > 690.5 > 5 a Amount added to well to achieve a 30 mm 2 hold as determined by PROBIT analysis as described in Examples 15 and 16 b No detectable activity up to 5 μg/well. c N.T. = not tested. It will be recognized that BPI.84 peptide was found to have bactericidal activity against E. coli J5 bacteria that was the molar equivalent to rBPI 23 . The results of heparin binding experiments for the BPI functional domain peptides of the invention are shown in representative examples in Figures 15a- 15e and Figure 16, and summarized in Table IX, wherein heparin binding data are expressed as affinity (nM) and capacity (ng). By plotting the amount of heparin bound versus increasing concentration of heparin, and fitting the data to standardized equations by non-linear least squares methods (GraFit, v.2.0, Εrithacus Software, London, England), both the binding constant (KM and capacity are calculated. 10 15 20 25 30 TABLE IX (cont'd) 10 15 20 25 30 TABLE IX (cont'd) 10 15 20 25 30 TABLE IX (cont'd) 10 15 20 25 30 An intriguing relationship was observed among representative BPI functional domain peptides when a multiple regression analysis was done using bactericidal activity as the predicted variable and heparin binding capacity and affinity { ,_) as the predictor variables. This analysis revealed that only heparin binding capacity was significantly related to bactericidal activity (heparin capacity, p = 0.0001 and heparin affinity, p = 0.6007). In other words, the amount of heparin that a given peptide embodiment can bind at saturation (i.e. capacity) has a significant relationship with bactericidal activity and not how soon a given peptide reaches 50% saturation in the heparin titration (i.e. affinity). From the data on LPS binding competition and neutralization, it also appears that capacity is most predictive of bactericidal activity. For examples, the results demonstrate that BPI.7, BPL29, BPI.30, BPI.46, BPI.47, BPI.48, BPI.63, BPI.65 (reduced), BPI.69, BPI.73, BPI.58, MAP.1 and MAP.2 have extremely high heparin capacity and also are highly bactericidal. Multiple antigenic peptides (MAP peptides) are multimeric peptides on a branching lysine core as described by Posnett and Tarn, 1989, Methods in Enzymology 178: 739-746. Conversely, BPI.2, BPI.4, BPI.8, BPI.14, BPI.53 and BPI.54 have low heparin binding capacity and accordingly have little or no bactericidal activity. BPI interdomain combination peptides BPI.30 (comprising domain II- domain III peptides) and BPI.74 (comprising domain Ill-domain π peptides) were compared for bactericidal activity against Gram-negative and Gram-positive bacteria, and for heparin binding and capacity. These results surprisingly showed that inverting the order of the peptides in the combination changed the relative activity levels observed. For example, BPI.74 was found to have greatly reduced bactericidal activity compared with BPI.30. Specifically, BPI.74 had 10-fold lower bactericidal activity against E. coli J5 bacteria, 50-fold lower bactericidal activity against E. coli Olll:B4 bacteria, and 3.5-fold lower bactericidal activity against S. aureus. A 2-fold reduction in heparin binding capacity and a 2-fold increase in heparin affinity, was also observed. Other bactericidal and endotoxin binding proteins were examined for heparin binding activity. Cecropin A, magainin II amide, Polymyxin B peptide and Limulus anti-LPS factor (LALF) were assayed in the direct heparin binding assay described in Example 3. The magainin II amide (Sigma, St. Louis, MO) exhibited the highest heparin binding capcity (437.7 ng heparin/2 μg peptide, 1^=3.17 μM) relative to cecropin A (Sigma, 242 ng/2 μg, K d =395 nM), LALF (Assoc. of Cape Cod, Woods Hole, MA, 195.3 ng/2μg peptide, K d = 1.29 μM), and PMB peptide (Bachem Biosciences, Philadelphia, PA, 58.0 ng/2 μg peptide, K < ,=309 mM). The magainin II amide is a substitution variant of the natural magainin sequence, where 3 alanines have been substituted at positions 8, 13, 15. The magainin II amide is reported to have less hemolytic activity than the natural magainin sequence. The above results support the relationship between heparin binding, LPS binding and bactericidal activities demonstrated by the BPI peptide data and suggest that other LPS binding proteins will also bind to heparin. The more active bactericidal proteins, cecropin A and magainin π amide, correspondingly, have the highest heparin binding capacity of this series of other LPS binding proteins. One type of BPI functional domain peptide addition variant incorporates the addition of D-alanine-D-alanine to either the amino- or carboxyl-terminus of a BPI functional domain peptide. The rational for this approach is to confer greater Gram-positive bactericidal activity with the addition of D-alanine. The cell wall biosynthesis in Gram-positive bacteria involves a transpeptidase reaction that specifically binds and utilizes D-alanine-D-alanine. Beta-lactam antibiotics such as the penicillins effectively inhibit this same reaction. Incorporation of D-alanine- D-alanine onto an active bactericidal peptide should target the peptide to the actively growing cell wall of Gram-positive bacteria. In the domain π substitution series of BPI functional domain peptides, an unexpected increase was observed when LySgs was substituted by alanine (BPI.24) . A subsequent phenylalanine substitution at position 95 (BPI.73) resulted in improved activity compared with the alanine substitution species. Surprisingly, substitution at position 95 with D-Phe (BPI.76) resulted in dramatically reduced activity, to levels lower than the original peptide (BPI.2). This isomer effect demonstrates that the interactions of this peptide is stereospecific, and implies that BPI.73 can adopt a more active conformation compared with BPI.76. Such stereospecificity, particularly after the phenomenon has been investigated at other residues, provides an important determinant for pharmacophore development. Peptides derived from the functional domains of BPI as defined herein have been utilized to determine that the hydrophobic amino acids (especially tryptophan) are most critical for optimal activity. This finding was unexpected due the cationic nature of BPI. In fact, for domain II, when a lysine is replaced by an alanine or phenylalanine, the activity increases dramatically (BPI.24, BPI.73). Combinations of functional domain peptides can also increase the potency of individual peptide constructs, including combinations of the most active substitution peptides from the three domains. The purity of each newly synthesized peptide was determined by analytical reverse-phase HPLC using a VYDAC C-18 column (25 cm x 4.6 mm, 5μm particle size, 30 nm pore size; Separation Group, Hesperia, CA). HPLC was performed using 5% acetonitrile/0.1 % trifluoroacetic acid (TFA) in water as mobile phase A, and 80 % acetonitrile/0.065 % TFA as mobile phase B. The eluate was monitored spectrophotometrically at 220 nm. The flow rate was 1.0 mL/min. Gradient elution conditions were selected to give optimum resolution for each peptide. Purity was expressed as the percentage that the main peak area contributed to the total peak area (see Table X). Purity and identity of the new synthesized peptides were also determined by electrospray ionization mass spectrometry using a VG Biotech Bio-Q mass spectrometer. Table X presents a summary of the purity analyses of exemplary peptides of the invention by mass spectroscopy and HPLC. TABLE X Peptide # Protein AA Segment MS % HPLC % Purity Purity BPI.l BPI.2 37.2 BPI.3 BPI.4 BPI.5 BPI.6 BPI.7 40.9 BPI.8 BPI.9 BPI.10 94-99, 90-99, 90-99 and 93-99, 90-99, 90-99 BPI.11 BPI.12 BPI.13 BPI.13P BPI.14 BPI.15 BPI.16 BPI.17 BPI.18 BPI.19 BPI.20 BPI.21 TABLE X (cont'd) Peptide # Protein AA Segment BPI.23 85-99, A @ 94 (Q) BPI.24 85-99, A @ 95 (K) BPI.25 85-99, A @ 96 (R) BPI.26 85-99, A @ 97 (F) BPI.27 85-99, A @ 98 (L) BPI.28 85-99, A @ 99 (K) BPI.29 (148-161) x 2 BPI.30 90-99,148-161 BPI.30-P 90-99,148-161 BPI.31 148-161, A @ 148 (K) BPI.32 148-161, A @ 149 (S) BPI.33 148-161, A @ 150 (K) BPI.34 148-161, A @ 151 (V) BPI.35 148-161, A @ 152 (G) BPI.36 148-161, A @ 153 (W) BPI.37 148-161, A @ 154 (L) BPI.38 148-161, A @ 155 (I) BPI.39 148-161, A @ 156 (Q) BPI.40 148-161, A @ 157 (L) BPI.41 148-161, A @ 158 (F) BPI.42 148-161, A @ 159 (H) BPI.43 148-161, A @ 160 (K) BPI.44 148-161, A @ 161 (K) BPI.45 85-99, A @ 94(Q)&95(K) BPI.46 (99-90)x2, A @ 1st 94(Q)&95(K) TABLE X (cont'd) Peptide # BPI.47 BPI.48 BPI.54 BPI.55 BPI.56 BPI.58 BPI.59 BPI.60 BPI.61 BPI.63 BPI.65 Rd BPI.65 Ox BPI.66 BPI.67 BPI.69 BPI.70 BPI.71 BPI.72 BPI.73 BPI.74 BPI.75 BPI.76 TABLE X (cont'd) TABLE X (cont'd) BPI.13, as well as other selected peptides, were purified using a semi- preparative reverse-phase VYDAC C-18 column (25 cm x 10 mm, 10 μ particle size, 30 nm pore size). The following gradient was used to purify BPI.13: 26.7%B to 33%B/30 min. at a flow rate of 2.0 mL/min. BPI.13 was dissolved in mobile phase A at a concentration of 8.8 mg/mL and injected in a volume in 0.5 mL. Three separate injections were made and the main peak from each injection was collected. The collected material was combined and evaporated to dryness using a SpeedVac. The purity of the recovered material (which will be referred to as BPI.13P, for purified) was determined with the analytical reverse-phase system and gradient elution conditions described above. Based on this analysis, BPI.13P was 98% pure. Purity and identity of BPI.13P was also determined by electrospray ionization mass spectometry using a VG Biotech Bio-Q mass spectrometer. The observed moleuclar mass was 1711.0 (the predicted mass was 1711.1). No impurities were detected by mass spectrometry. Recovery of BPI.13P was 55 % , assuming that the desired peptide constituted 69% of the starting material. When peptides of the invention were further purified, as described above, the magnitude of the tested biological activity of the peptides, e.g. , BPI.13P and BPI.30P, were found to increase when chemical purity was increased. This indicated that the observed biological activity was due to the peptide itself. In particular, the completely novel and unexpected antifungal activity of BPI.13 against Candida albicans (see Example 16), with a purity of about 69%, was further increased when the purity of the peptide preparation was increased to 98 % . EXAMPLE 20 Analysis of BPI Functional Domain Peptides using Binding and Neutralization Assays A. LPS Binding Assays BPI functional domain peptides were subjected to LPS binding assays. The first of these assays was performed as described in Gazzano-Santoro et ah, supra. Briefly, a suspension of E. coli strain J5 Lipid A was sonicated and diluted in methanol to a concentration of 0.2μg/mL, and then 50μL aliquots were adsorbed to wells (Immulon 2 Removawell Strips, Dynatech). Following overnight incubation at 37°C, the wells were blocked with 215μL of a solution of D- PBS/0.1 % BSA for 3 hr at 37 °C. Thereafter, the blocking buffer was discarded, the wells were washed with a solution of 0.05% Tween-20 in D-PBS (D-PBS/T) and incubated overnight at 4°C with 50μL of a solution of IJ-rBPI^ in D-PBS/T (a total of 234,000 cpm at a specific activity of 9.9 μCi/μg) and increasing concentrations of BPI functional domain peptides. After this incubation, the wells were washed three times with D-PBS/T and the bound radioactivity counted using a gamma counter. Binding to wells treated with D-PBS/BSA was considered non¬ specific background binding and was subtracted from the total radioactivity bound in each well to yield the amount of specifically-bound radioactivity. The results of these experiments are shown in Figures 17a (where the concentration of each peptide is given in nM) and 17b (the identical results, with the concentration of peptide given in μg/mL). Competition experiments using unlabeled rBP^ are shown for comparison. These results demonstrate that all of the tested peptides have some capacity to compete with rBPI 23 for LPS binding, to differing degrees. This experiment was repeated, comparing the LPS binding affinity of BPI.10 with rBPI 23 , using twice the amount of [ 125 rj-rBPI 23 (a total of 454,000 cpm, specific activity 10 μCi/μg) and in the presence or absence of whole blood. These results are shown in Figure 18, and demonstrate that, on a molar basis, BPI.10 is within a factor of 2 as potent as rBP^ in competing with radiolabeled rBP^ in this assay. The experiment was repeated using peptides BPI.7, BPI.29 and BPI.30, as in the first experiment described above except that a total of 225,000 cpm of [ 125 I - rBPI 23 was used and Lipid A was plated at a concentration of 0.5 mg/mL. The results of this experiment are shown in Figure 19, and show that, on a molar basis, these peptides are 6- to 10-fold less potent that unlabeled rBPI 23 in binding Lipid A. A second binding assay was developed, wherein radiolabeled recombinant LPS binding protein ([ 125 I]-rLBP) was used instead of radiolabeled rBPI 23 in competition experiments with BPI functional domain peptides BPI.2, BPI.3, BPI.4, BPI.5, BPI.7, BPI.13, BPI.14, BPI.29, BPI.30 and BPI.48. rBPI, rBPI 2 ιΔcys, and rLBP 25 were included in these assays as controls. In these experiments, Lipid A was adsorbed to the wells at a concentration of 0.7 μg/mL in methanol. Incubation of radiolabeled rLBP (a total of 650,000 cpm and a specific activity of 3.45 μCi/μg) was performed for 2.5 hr at 37°C in the presence of BPI peptides in a series of increasing concentrations. These results are shown in Figures 20a and 20b. IC 50 values (i.e. , the concentration at which Lipid A binding of radiolabeled rLBP 25 is inhibited to one half the value achieved in the absence of the peptide) are shown in accompanying Table XI. Peptide rBPI rBPI 21 Δcys BPI.7 BPI.29 BPI.48 BPI.30 BPI.3 rLBP 25 BPI.13 BPI.2 BPI.5 In a third binding assay, a number of BPI functional domain peptides were tested for their ability to bind to radiolabeled LPS following incubation with human endothelial cells (HUVEC). This assay measures the ability to bind LPS once the BPI peptides are bound to HUVEC cells. HUVEC cells were incubated in the presence of various BPI peptides at a concentration of either 1 μg/mL or 3 μg/mL for 3 hr at 4°C in 500 μL of a solution of D-PBS/BSA. Following this incubation, the cells were washed twice with ice-cold D-PBS/BSA and then incubated for an additional 2.5 hr at 4°C in 500 μL of a solution of [ 1 5 rj-RaLPS (a total of 340,000 cpm at a specific activity of 4.6 x 10 6 cpm/μg) in D-PBS/BSA. The wells were washed three times with D-PBS/BSA, solubilized in 500 μL of 1M NaOH and the lysates counted using a gamma counter. These results, shown in Figure 21, indicate that BPI.29 and BPI.30 retain the capacity to bind LPS while bound to HUVEC cells. B. LPS Neutralization Screening Assay of BPI Functional Domain Peptides using TNF Cellular Toxicity A screening assay for LPS neutralization was developed using a tumor necrosis factor (TNF) cellular toxicity assay. A human monocytic cell line (THP- 1; accession number TIB202, American Type Culture Collection, Rockville, MD) grown in media supplemented with Vitamin D produce TNF upon stimulation with LPS in a dose-dependent fashion. Mouse fibroblasts (L929 cells; ATCC No.: CCL1) are sensitive to TNF-mediated cell killing, and this cell killing is also dose- dependent. Thus, the extent of cell killing of L929 cells provides a sensitive assay for the degree of TNF induction in THP-1 cells, which in turn is a sensitive indicator of the amount of free LPS in contact with the THP-1 cells. LPS binding and neutralization by BPI functional domain peptides or rBP^ reduces the amount of free LPS in contact with THP-1 cells, which reduces the amount of TNF produced, which in turn reduces the amount of L929 cell killing in a standardized assay. Thus, the following assay provides a sensitive method for assessing the LPS binding and neutralization capacity of the BPI functional domain peptides of this invention. THP-1 cells were grown in RPMI media (GIBCO, Long Island, NY) supplemented with 10% FCS and Vitamin D in spinner culture for 3 days to a density of about 150,000 cells/mL. Cells were then plated in a round-bottomed 96- well culture plate at a density of 100,000 cells/well and incubated in RPMI media without Vitamin D or FCS in the presence of 5ng/mL E. coli 01113 LPS for 6 hr at 37° C. Experimental control wells also contained varying amounts of rBP^ or BPI functional domain peptides, in concentrations varying from about 0.1 μg/mL to about 100 μg/mL. After this incubation, the plates were centrifuged at about 600 x g to pellet the cells, and 50 μL of the supernatant were added to a 96- well flat bottomed culture dish prepared in parallel with 50,000 L929 cells per well in 50 μL RPMI/ 10% FCS. L929 cells were prepared by monolayer growth in RPMI/ 10% FCS media to a density of about 1 million cells per dish, then split 1:2 on the day before the experiment and allowed to grow overnight to about 70% confluence on the day of the experiment. Actinomycin D was added to the 70% confluent culture to a final concentration of 1 μg/mL 20 min prior to plating in 96- well plates. L929 cell plates were incubated in the presence of the THP-1 supernatant for about 16 hr (overnight) at 37 °C under standard conditions of mammalian cell growth. To each well was then added 20 μL of a solution prepared by diluting 100 μL of phenazine methylsulfonate in 2 mL CellTitre 96™ AQ,, ^ , solution (Promega, Madison, WI), containing 3-[(4,5-dimethyl)-thiozol-2-yl]-5-(3-carboxymethoxyphenyl)-2-(4- sulfonyl)-2H-tetrazolium (inner salt). The cultures were allowed to incubate for 2-4 hr at 37 °C and then analyzed spectrophotometrically to determine the optical absorbance at 490nm (A490). Experimental results were evaluated relative to a semilog standard curve prepared with known amounts of TNF, varying from about 10 ng/mL to about 10 mg/mL. The results of these experiments are shown in Figures 22a-22h. Figure 22a shows the relationship between A490 and TNF concentration in cultures of L929 cells in the presence and absence of 5 ng/mL LPS. These results show about the same linear relationship between A490 and concentration of TNF whether or not LPS was present in the assay media. Figure 22b illustrates an experiment where TNF was incubated with L929 cells in the presence of increasing amounts of heparin. These results show a constant and characteristic A490 for TNF at concentrations of 1 ng/mL and 0.1 ng/mL, indicating that heparin does not affect L929 cell killing by TNF. Figure 22c illustrates a control experiment, showing that rBPI 21 Δcys decreased the amount of TNF-mediated L929 cell killing when incubated at the indicated concentrations in cultures of THP-1 cells in the presence of 5 ng/mL LPS. Figure 22d shows that heparin could compete with LPS for binding with rBPI 2 ,Δcys, by inhibiting the BPI-mediated inhibition of LPS- stimulated TNF production by THP-1 cells, as measured by the L929 cell killing assay. Figure 22e is a standard curve of A490 versus TNF as a measure of TNF- mediated L929 cell killing; Figure 22g shows the linearity of the standard curve in a semilog plot over a TNF concentration range of about three logs (about 1000- fold). Figure 22f shows the THP-1 cell dependence of the assay, wherein detectable amounts of TNF were most readily produced using about 100,000 THP- 1 cells and LPS at a concentration of at least 5 ng/mL. Finally, Figure 22h shows that the assay was found to be dependent on THP-1 cell production of TNF in response to LPS stimulation; human histiocytic lymphoma cells (U937; ATCC No.: CRL1593) produced no detectable TNF when substituted in the assay for THP-1 cells. This assay was used to analyze LPS binding and neutralization capacity of a number of BPI functional domain peptides of the invention. These results are shown in Table XQ, and indicate that each of the peptides tested had the capacity to inhibit LPS-stimulated TNF production in THP-1 cells, as measured by TNF- mediated L929 cell killing. C. LPS Neutralization Screening Assay of BPI Functional Domain Peptides using a Cellular NO Production Assay An additional LPS neutralization screening assay for BPI functional domain peptides was developed using an assay for NO production in mouse cells treated with LPS (see Lorsbach et ah, 1993, J. Biol. Chem. 268: 1908-1913). In this assay, mouse RAW 264.7 cells (ATCC Accession No. T1B71) were treated with bacterial LPS. The cells were incubated in 96-well plates and stimulated for 2 hours with E. coli 0113 LPS or zymosan, in the presence or absence of y- interferon, rLBP, fetal bovine serum (FBS) or normal human serum (NHS), or rBPI 21 Δcys. After this incubation, the cells were washed with fresh media and incubated overnight in media containing 10% FCS. The NO released from the cells accumulated in the media and spontaneously converted to nitrite. This nitrite was assayed in situ by the Griess reaction, as follows. The nitrite was reacted with the primary amine of an added sulfanilamide and formed a diazonium salt. This salt was then reacted with added naphthylethylenediamine to form a red azo-dye. The Griess reaction was performed at room temperature in about 10 minutes. The amount of produced NO was estimated from a standard curve of Griess reaction products determined spectrophotometrically as Absorbance at a wavelength of 550nm. The results of this assay are shown in Figures 23a to 23c. Figure 23a shows the dependence of NO production on the presence of 7-interferon. This interferon effect was found to saturate at a concentration of lOOU/mL. Figure 23b shows the dependence of LPS-stimulated NO production on the presence of LBP, either added as purified recombinant protein or as a component of FBS or NHS supplements of the cell incubation media. Figure 23c shows rBPI 23 -mediated inhibition of LPS-stimulated NO production, having an IC 50 of 30-100 ng/mL. These results demonstrated that this assay is a simple, inexpensive and physiologically-relevant assay system for assessing the LPS-neutralizing activity of BPI and BPI functional domain peptides disclosed herein. The results of such assays performed with BPI functional domain peptides are shown in Figures 24a-24g wherein the background production of NO by unstimulated cells is designated as "NO LPS". Figures 24a and 24b show inhibition of NO production stimulated by zymosan and LPS, respectively, by rBPI, rBPI 2 ιΔcys and rLBP 25 . No inhibition of zymosan-stimulated NO production was seen at any concentration of BPI protein (Figure 24a). In contrast, LPS- stimulated NO production was inhibited in a concentration-dependent manner by incubation with these rBPI-related proteins (Figure 24b). Figure 24c (zymosan) and Figure 24d (LPS) shows the effects on NO production by RAW 264.7 cells of incubation with BPI.2, BPI.3, BPI.4, BPI.7 and BPI.14; rBPI 21 Δcys is also shown for comparison. As shown with native BPI, zymosan-stimulated NO production was not inhibited by incubation with any of the BPI functional domain peptides (with the possible exception of a small amount of inhibition by BPI.7 at high concentrations; Figure 24c). LPS-stimulated NO production, on the other hand, was inhibited efficiently by rBPL Δcys, and to a lesser degree by BPI.3 and BPI.7 (Figure 24d). This experiment was repeated using BPI.5, BPI.13, BPI.29 and BPI.30, with rBPI 2 ιΔcys analyzed in parallel for comparison. Zymosan-stimulated NO production by RAW 264.7 cells was found to be inhibited by BPI.30 at high ( ~ 100 μg/mL) concentrations; neither any of the other BPI functional domain peptides nor rBPI 21 Δcys showed any inhibition of zymosan-stimulated NO production (Figure 24e). LPS-stimulated NO production was inhibited efficiently by rBPI 21 Δcys, and to varying and lesser degrees by all of the BPI functional domain peptides tested in this experiment (Figure 24f). The IC 50 values (i.e. , the concentration of inhibitor at which zymosan or LPS-stimulated NO production by RAW 264.7 cells is reduced to one-half its value in the absence of the inhibitor) for the BPI proteins and peptides were calculated from these experiments and are showed in Figure 24g. With the exception of BPI.30, no significant inhibition of zymosan-mediated NO production was found for either the BPI functional domain peptides or rBPI 21 Δcys, rBPI or rLBP in these experiments; the IC 50 of BPI.30 for inhibition of zymosan-stimulated NO production was found to be between 10 and 100 μg/mL. BPI.3, BPI.5, BPI.13, BPI.29 and BPI.30 were found to have detectable levels of LPS neutralization in this assay, and the relative IC 50 values for these peptides are shown in Figure 24g. D. LPS Neutralization Screening Assay of BPI Functional Domain Peptides using a Cellular Proliferation Assay An additional LPS neutralization screening assay for evaluation of BPI functional domain peptides was developed. This sensitive assay for inhibition of cellular proliferation in mouse cells treated with LPS can also be utilized for quantitation of LPS levels in human plasma upon development of a standard curve. In this assay, mouse RAW 264.7 cells (ATCC Accession No. T1B71), maintained in RPMI 1640 media (GIBCO), supplemented with lOmM HEPES buffer (pH 7.4), 2mM L-glutamine, penicillin (lOOU/mL), streptomcin (lOOμg/mL), 0.075% sodium bicarbonate, 0.15M2-mercaptoethanoland 10% fetal bovine serum (Hyclone, Inc. , Logan, UT), were first induced by incubation in the presence of 50U/mL recombinant mouse 7-interferon (Genzyme, Cambridge, MA) for 24h prior to assay. Induced cells were then mechanically collected and centrifuged at 500 x g at 4°C and then resuspended in 50mL RPMI 1640 media (without supplements), re-centrifuged and again resuspended in RPMI 1640 media (without supplements). The cells were counted and their concentration adjusted to 2 x 10 5 cells/mL and lOOμL aliquots were added to each well of a 96-well microtitre plate. The cells were then incubated for about 15 hours with E. coli 0113 LPS (Control Standard, Assoc. of Cape Cod, Woods Hole, MA), which was added in lOOμL/well aliquots at a concentration of 1 ng/mL in serum-free RPMI 1640 media (this concentration being the result of titration experiments in which LPS concentration was varied between 50pg/mL and lOOng/mL). This incubation was performed in the absence or presence of BPI functional domain peptides in varying concentrations between 25ng/mL and 50μg/mL. Recombinant human BPI was used as a positive control at a concentration of lμg/mL. Cell proliferation was quantitatively measured by the addition of lμCi/well [ 3 H]-thymidine 5 hours after the time of initiation of the assay. After the 15-hour incubation, labeled cells were harvested onto glass fiber filters with a cell harvester (Inotech Biosystems, INB- 384, Sample Processing and Filter Counting System, Lansing, MI.). The results of this assay are shown in Figures 26a-26c. Figure 26a shows the dependence of LPS-mediated inhibition of RAW 264.7 cell proliferation of the presence of LBP, added to the reaction mixture either as a component of serum or as recombinant LBP (at a concentration of lμg/mL) . Figures 26b and 26c illustrate patterns of BPI functional domain peptide behavior found in the above assay. BPI.5 displayed an EC 50 (i.e. , the peptide concentration at which the growth inhibitory effect of LPS was reversed by 50%) of 5.3 ± 0.6 μg/mL. BPI.81 was unable to reverse the growth inhibitory effect of LPS on RAW 264.7 cells, but showed additional growth inhibition with an IC 50 (i.e. , the peptide concentration at which RAW cell growth was inhibited by 50% from the value without added peptide) of 14 ± 0.2 μg/mL. BPI.98 showed an EC 50 of 0.16 ± 0.08 μg/mL and an IC 50 of 16.5 + 1.9 μg/mL. Finally, BPI.86 showed an EC 50 of 0.13 ± 0.04 μg/mL and an IC 50 of 37.5 ± 12.5 μg/mL. Results from all peptides tested with this assay are shown in Table Xm. TABLE Xffl BPI peptide Sequence BPI.2 IKISGKWKAQKRFLK BPI.5 HVHISKSKVGWLIQLFHKKIE BPI.7 KWKAQKRFLKKWKAQKRFLK BPI.10 QKRFLKKWKAQKRFLKKWKAQKRFLK BPI.13 KSKVGWLIQLFHKK BPI.13p KSKVGWLIQLFHKK BPI.29 KSKVGWLIQLFHKKKSKVGWLIQLFHKK BPI.30 KWKAQKRFLKKSKVGWLIQLFHKK BPI.46 KWKAAAKRFLKKWKAQKRFLK BPI.47 KWKAQKRFLKKWKAAAKRFLK BPI.48 KWKAAAKRFLKKWKAAAKRFL BPI.63 IKISGKWKAQKRFLKKSKVGWLIQLFHKK BPI.69 KWKAAARFLKKWKAAARFLKKWKAAARFLK BPI.73 IKISGKWKAQFRFLK BPI.74 KSKVGWLIQLFHKKKWKAQKRFLK BPI.76 IKISGKWKAQFnRFLK BPI.77 IKISGKWKAQWRFLK BPI.80 IKISGKWKAQA^^^RFLK BPI.81 IKISGKWKAFKRFLK 14.0+0.2 TABLE Xffl (cont'd) BPI peptide Sequence BPI.82 KSKVGWLIQLWHKK BPI.83 KSKVGWLIQLA,. α .^ hthyl) HKK BPI.84 IKISGKAø. (1 . MphthyI) KAQFRFLK BPI.85 KSKVLWLIQLFHKK . BPI.86 KSKVGWLILLFHKK . BPI.87 KSKVGWLIQLFLKK BPI.88 IKISGKWKAFFRFLK BPI.89 IKISGKA3-(l-naphthyl)KAFKRFLK BPI.90 IKISGKAp. α . ωphthyl) KAFFRFLK BPI.91 KSKVGWLIFLFHKK BPI.92 KSKVGWLIKLFHKK BPI.93 IKISGKAø. α . Mph I) KAQFRFLKKSKVGWLIQLFHKK BPI.94 KSKVGWLIQLFFKK BPI.95 KSKVFWLIQLFHKK BPI.96 KSKVGWLIQLFHKF BPI.97 KSKVKWLIQLFHKK BPI.98 IKISGKAø. α . ωphΛyl) KAQFRFLKKSKVGWLIFLFHKK MAP. l (3-alanyl-Nα,Ne-substituted-[Nα,Ne(BPI.2)lysyl]lysine) rBPI 21 Δcys No proliferation decrease up to 50 μg/ml. E. LPS Neutralization Assay based on Inhibition of LPS-induced TNF Production in Whole Blood LPS neutralization by BPI functional domain peptides of the invention was assayed in whole blood as follows. Freshly drawn blood from healthy human donors was collected into vacutainer tubes (ACD, Rutherford, N.J.) Aliquots of blood (170μL) were mixed with 10μL Ca + + -, Mg ++ -freePBS containing 2.5ng/mL E. coli 0113 LPS, and with 20μL of varying concentrations of the BPI peptides of the invention ranging in concentration from 0.5-50μg/mL. These mixtures were then incubated for 4h at 37°C, and then the reaction stopped by the addition of 55μL ice-cold Ca + + -, Mg ++ -free PBS, followed by centrifugation at 500 x g for 7min. Supernatants were then assayed for TNF levels using a commercial ELISA kit (Biokine™ ELISA Test, T-cell Sciences, Cambridge, MA). The results of these experiments with representative peptides using whole blood samples from two different donors are shown in Figure 27 and Table XIV. Figure 27 shows a comparison of TNF inhibition by BPI functional domain peptides BPI.7, BPI.13 and BPI.29; results obtained using rBPI 21 Δcys are shown for comparison. These results are quantitated as IC 50 values in Table XIV, and compared with LPS neutralization as assayed using NO production by RAW 264.7 cells as described in Section C above. TABLE XTV F. LPS and Heparin Binding Assays using Tryptophan Fluorescence Quenching The naturally-occurring amino acid tryptophan can emit light (i.e. , it fluoresces) having a wavelength between 300 and 400nm after excitation with light having a wavelength of between about 280nm and 290 nm, preferably 285nm. The amount of emitted light produced by such fluorescence is known to be affected by the local environment, including pH and buffer conditions, as well as binding interactions between proteins and other molecules. Some BPI functional domain peptides derived from domains II and HI contain tryptophan residues, and tryptophan fluorescence was used to assay binding interactions between the BPI functional domain peptides of the invention and LPS or heparin. Tryptophan fluorescence of the BPI functional domain peptides of the invention was determined in the presence or absence of LPS or heparin using a SPEX Fluorolog fluorimeter. Samples were excited with 285nm light using a 0.25nm slitwidth. Emission wavelengths were scanned between 300-400nm using a 1.25nm slitwidth. Data were accumulated as the average of three determinations performed over an approximately 5 min time span. Samples were maintained at 25 °C or 37 °C during the course of the experiments using a circulating water bath. Crab endotoxin binding protein (CEBP), a protein wherein the intrinsic fluorescence of tryptophan residues is affected by binding to LPS, was used as a positive control. (See Wainwright et a , 1990, Cellular and Molecular Aspects of Endotoxin Reactions. Nowotny et a , eds. , Elsevier Science Publishing B. V. , The Netherlands, pp. 315-325). The results of these experiments are shown in Table XV. K d values were determined by Scatchard-type Stern- Volmer plots of the quenching data as the negative inverse of the slope of such plots. Comparing the data for BPI.10, BPI.46 and BPI.47, it is seen that as the Kj decreased (indicating an increase in avidity for LPS), the percent fluorescence quenching increased. The differences between these peptides include replacement of basic and polar amino acid residues with non- polar residues in BPI.48 as compared with BPI.10. In contrast, as the K,, of heparin binding decreased, a corresponding increase in the percentage of fluorescence quenching was not detected. This result may indicate fundamental differences between the site or nature of heparin binding compared with LPS binding. CEBP (LALF) experiments were performed at 25 °C G. Neutralization Assay Of Heparin-Mediated Lengthening of Thrombin Time The effect of BPI functional domain peptides on heparin-mediated lengthening of thrombin time, i.e., the time required for clotting of a mixture of thrombin and plasma, was examined. Thrombin time is lengthened by the presence of endogenous or exogenous inhibitors of thrombin formation, such as therapeutically administered heparin. Agents which neutralize the anti-coagulant effects of heparin will reduce the thrombin time measured by the test. In these experiments, thrombin clotting time was determined using a MLA Electra 800 Coagulation Timer. Reconstituted plasma (200 μL, Sigma Chemical Co., No. 855-10) was incubated at 37°C for two minutes in a reaction cuvette. Thrombin Clotting Time reagent (100 μL, Baxter Diagnostics Inc. , B4233-50) was added to the reaction cuvette after incubation and clotting time was then measured. Heparin sodium (13 μL, 40 μg/mL in PBS, Sigma Chemical Co., H3393) and exemplary BPI functional domain peptides (10 μL of various dilutions from about 0.05 μg/ml to about 10 μg/ml) were added to the reaction cuvette prior to plasma addition for testing of the effects of these peptides on thrombin clotting time. TCT clotting time (thrombin time) was measured using the BPI peptides indicates and the results are shown in Figure 28 and Table XVI. These results shown in Figure 28 and Table XVI below demonstrate that the tested BPI functional domain peptides neutralized heparin, as shown by inhibition of the heparin-mediated lengthening of thrombin time. The IC 50 of this inhibition was quantitated and is shown in Table XVI. Heparin Neutralization Assay based on Inhibition of Heparin/FGF- Induced Angiogenesis into Matrigel ® Basement Membrane Matrix In Vivo BPI functional domain peptides of the invention are assayed for their ability to inhibit heparin-induced angiogenesis in vivo in mice. Liquid Matrigel ® (Collaborative Biomedical Products, Inc. , Bedford, MA) is maintained at 4°C and angiogenic factors are added to the gel in the liquid state as described in Passaniti et ah (1992, Lab. Invest. £7: 519-528). Heparin (Sigma, St. Louis, MO) is dissolved in sterile PBS to various concentrations ranging from 1,250 - 10,000 U/mL. Recombinant fibroblast growth factor (bliFGF ; BACHEM Bioscience Inc. , Philadelphia, PA) is diluted to 200ng/mL with sterile PBS. A volume of 2.5μL dissolved heparin solution and 2.5μL recombinant bhFGF is added to 0.5mL Matrigel ® per mouse injection. BPI functional domain peptides are added to this Matrigel ® mixture at varying concentrations ranging from 0.5 to 50μg/mL (final concentration) in 10μL/ 0.5mL Matrigel ® aliquot per experimental animal. Ten μL sterile PBS is substituted for BPI functional domain peptides in Matrigel ® aliquots injected into control animals. Male C57BL/6J mice (Jackson Laboratory, Bar Harbor, ME) at 6-8 weeks of age are injected subcutaneously down the dorsal midline with 0.5mL aliquots of Matrigel ® prepared as described above. Seven days after injection, the Matrigel ® gels are excised and placed in 500μL Drabkm' s reagent (Sigma) . Total protein and hemoglobin content are determined for the gels stored in Drabkin's reagent after mechanical homogenization of the gels. Total protein levels are determined using a microplate assay that is commercially embodied in a kit (DC Protein Assay, Bio- Rad, Richmond, CA). Hemoglobin concentration is measured using Sigma Procedure #525 and reagents supplied by Sigma (St. Louis, MO) to be used with this procedure. Hemoglobin levels are expressed relative to total protein concentration. Gels to be used for histological staining are formalin-fixed immediately after excision from the animals rather than being placed in Drabkin's reagent. Formalin-fixed gels are embedded in Tissue-Tek O.C.T. compound (Miles, Inc., Elkhart, IN) for frozen sectioning. Slides of frozen sections are stained with hematoxylin and eosin (as described by Humason, 1979, Animal Tissue Techniques. 4th Ed. W.H. feeman & Co., San Fransisco, CA, Ch.9, pp 111-131). The effect of the BPI functional domain peptides of the invention are detected by microscopic examination of frozen stained sections for inhibition of angiogenesis relative to Matrigel ® gel slices prepared without added BPI peptides. The extent of angiogenesis inhibition is quantitated using the normalized amounts of hemoglobin found in BPI peptide-containing gel slices. EXAMPLE 22 Analysis of BPI Functional Domain Peptides in Chronic Inflammatory Disease: Collagen-Induced or Reactive Arthritis Models BPI functional domain peptides are administered for their effects in a collagen-induced arthritis model. Specifically, arthritis is induced in mice by intradermal immunization of bovine Type II collagen at the base of the tail according to the method of Stuart et a (1982, J. Clin. Invest. 69: 673-683). Generally, mice begin to develop arthritic symptoms at day 21 after collagen immunization. The arthritic scores of the treated mice are then evaluated in a blinded fashion over a period of 120 days for mice treated on each of days 21-25 with doses of either BPI functional domain peptides, control rBPI^ or rBPI, or buffer which are injected intravenously via the tail vein. Specifically, bovine Type II collagen (Southern Biotechnology Associates, Inc. , Birmingham AL) is administered via intradermal injection (0.1 mg/mouse) at the base of the tail on day 0 to groups of male mice (Mouse/DBA/ IJ), each weighing approximately 20-25 g. BPI functional domain peptides, and rBPI 23 and rBPI are dissolved in a buffer comprised of 0.5M NaCl, 20mM sodium acetate (pH 6.0) and diluted with PBS buffer for administration at various concentrations. PBS buffer alone (0.1 mL) is administered as a control. The collagen-induced arthritis model is also used to evaluate the performance of BPI functional domain peptides in comparison with protamine sulfate. Specifically, BPI peptides are dissolved in PBS as described above and administered at various concentrations. The other test materials are administered at the following dosages: protamine sulfate (Sigma Chemical Co., St. Louis, MO) (0.13 mg/mouse), thaumatin (0.12 mg/mouse), and PBS buffer (0.1 mL). Groups of mice receive test or control materials through intravenous injection via the tail vein on each of days 28 through 32 post-injection with collagen. BPI functional domain peptides are also administered to treat reactive arthritis in a Yersinia enterocolitica reactive arthritis model according to the method of Yong et al. (1988, Microbial Pathogenesis 4: 305-310). Specifically, BPI peptides are administered to DBA/2J mice which have previously been injected intravenously with Yersinia enterocolitica cWA 0: 8 T2 (i. e. , lacking the virulence plasmid according to Yong et ah, supra) at a dosage of 4 x 10 8 bacteria calculated to induce a non-septic arthritis in the mice. Groups of mice each receive test or control materials through intravenous injection via the tail vein. Borrelia burgdorferi is the pathogen responsible for Lyme Disease and associated arthritis and it possesses an LPS-like complex on its cell walls which is different from but structurally related to that of E. coli. The effect of administration of BPI functional domain peptides on inhibition of B. burgdorferi LPS in a Limulus Amoebocyte Lysate (LAL) inhibition assay is determined. Specifically, an LAL assay according to the method of Example 4 is conducted measuring the effect of BPI peptides on B. burgdorferi LPS administered at 2.5μg/mL and E. coli 0113 LPS administered at 2ng/mL. EXAMPLE 23 Analysis of BPI Functional Domain Peptides in Mouse Malignant Melanoma Cell Metastasis Model BPI functional domain peptides, protamine, or buffer controls are administered to test their efficacy in a mouse malignant melanoma metastasis model. Specifically, groups of C57BL/6J mice are inoculated with 10 s B16.F10 malignant melanoma cells via intravenous injection into the tail vein on day 0. BPI functional domain peptides in various concentrations are administered into the tail vein of test mice on days 1, 3, 6, 8, 10, 13, 15, 17, and 19. Protamine sulfate (0.13 mg/mouse) as a positive control, or PBS buffer (0.1 mL/mouse) as a negative control are similarly administered to additional groups of control mice. The animals are sacrificed via cervical dislocation on day 20 for observation of lung tissues. The lobes of each lung are perfused and inflated by injecting 3mL water into the lung via the trachea. Superficial tumor nodules are then counted with the aid of a dissecting microscope and the number of tumors found per group analyzed for statistically significant differences. EXAMPLE 24 Analysis of BPI Functional Domain Peptides in a Mouse Cerebral Capillary Endothelial Cell Proliferation Assay BPI functional domain peptides are tested for their effects in all endod elial cell proliferation assay. For these experiments, murine cerebral capillary endothelial cells (EC) as described in Bauer (1989, Microvascular Research 37: 148-161) are passaged in Medium 199 containing Earle's salts, L-glutamineand 2.2 g/L of sodium bicarbonate (GIBCO, Grand Island, NY), plus 10% heat inactivated fetal calf serum (FCS; Irvine Scientific, Irvine, CA) and 1 % penicillin/ streptomycin (GIBCO). Harvesting of the confluent cells is performed by trypsinization with trypsin-EDTA (GIBCO) for 3 minutes. Trypsinization is stopped by adding 10 mL of the passage medium to the flask. Proliferation assays are performed on freshly harvested EC in standard flat bottom 96-well microtiter plates. A final volume of 200 μL/well is maintained for each well of the assay. A total of 4 x 10 4 EC cells is added to each well with varying concentrations of BPI peptides, or buffer control. After 48 hours of culture in a 5% CC^ incubator, 1 μCi of [ 3 H] thymidine in 10 μL of Medium 199 is added to each well. After a 24 hour pulse, the EC cells are harvested by trypsinization onto glass microfiber filters and incorporated [ 3 H]thymidine is quantitated with a gas proportional solid phase beta counter. Direct binding studies of BPI peptides on EC cells are performed by harvesting the 10-times passaged cells from a confluent flask and resuspending the trypsinized cells in 12.5 mL of culture medium. Then, 0.5mL of the cell suspension is added to each well of a standard 24 well tissue culture plate and incubated overnight. The plate is washed with 0.1 % bovine serum albumin in phosphate buffered saline containing calcium and magnesium (GIBCO). After washing, 0.5mL BSA/PBS is added per well. Concentration dependent inhibition of EC cell proliferation is measured in terms of decreases in [ 3 H] -thymidine uptake. EXAMPLE 25 Analayis of BPI Function Domain Peptides in Animal Models A. Analysis in a Mouse Endotoxemia Model BPI functional domain peptides are tested for their efficacy in a mouse experimental endotoxemia model. Groups of at least 15 mice are administered an intravenous injection of endotoxin (e.g. , E. coli Olll:B4, Sigma Chemical Co., St. Louis, MO) at a LD^ dosage (e.g. , 40 mg/kg). This is followed by a second intravenous injection of the test peptide in varying concentrations from about 0.1 mg/kg to about 100 mg/kg, preferably in the range of about 1 to 50 mg/kg. Injections of buffer without added peptide are used in negative control mice. The animals are observed for 7 days and mortality recorded. The efficacy of the peptides of this invention is measured by a decrease in endotoxemia-associated mortality in peptide-injected mice as compared with control mice. B. Analysis in a Mouse Peritonitis Model BPI functional domain peptides are tested for their efficacy in a mouse model of acute peritonitis. Groups of at least 15 mice are challenged with 10 7 live E. coli bacteria strain O7:Kl in 0.5 mL and then treated with 1.0 mL of a solution of BPI functional domain peptides at varying concentrations from about 0.1 mg/kg to about 100 mg/kg. Injections of buffer without added peptide are used in negative control mice. The animals are observed for 7 days and mortality recorded. Effective BPI functional domain peptides show a decrease in mortality of test group mice compared with control group mice. EXAMPLE 26 Therapeutic Use of BPI Functional Domain Peptides in a Human In vivo Endotoxin Neutralization Model A controlled, double-blind crossover study is designed and conducted as in co-owned, copending U.S. Patent Application Serial No. 08/188,221 filed January 24, 1994, to investigate the effects of BPI functional domain peptides in humans rendered endotoxemic by intravenous infusion of bacterial endotoxin. It should be understood that the foregoing disclosure emphasizes certain specific embodiments of the invention and that all modifications or alternatives equivalent thereto are within the spirit and scope of the invention as set forth in the appended claims. SEQUENCE LISTING ) GENERAL INFORMATION : (i) APPLICANT: (A) NAME: Xoma Corporation (B) STREET: 2910 Seventh Street (C) CITY: Berkeley (D) STATE: California (E) COUNTRY: USA (F) POSTAL CODE (ZIP): 94710 (G) TELEPHONE: (510)-644-1170 (H) TELEFAX: (510)-469-7571 (ii) TITLE OF INVENTION: Biologically Active Peptides from Functional Domains of Bactericidal/Permeability-Increasing Protein and Uses Thereof (iii) NUMBER OF SEQUENCES: 98 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Allegretti S. Witcoff, Ltd. (B) STREET: 10 South Wacker Drive, Suite 3000 (C) CITY: Chicago (D) STATE: Illinois (E) COUNTRY: USA (F) ZIP: 60606 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentin Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: US (B) FILING DATE: ll-MAR-1994 (C) CLASSIFICATION: (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Noonan, Kevin E (B) REGISTRATION NUMBER: 35,303 (C) REFERENCE/DOCKET NUMBER: 93,1133 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: 312-715-1000 (B) TELEFAX: 312-715-1234 (C) TELEX: 910-221-5317 (2) INFORMATION FOR SEQ ID NO:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "Domain I" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: Ala Ser Gin Gin Gly Thr Ala Ala Leu Gin Lys Glu Leu Lys Arg lie 1 5 10 15 Lys lie Pro Asp Tyr Ser Asp Ser Phe Lys lie Lys His 20 25 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 30 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (i ) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.14" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Gly Thr Ala Ala Leu Gin Lys Glu Leu Lys Arg lie Lys lie Pro Asp 1 5 10 15 Tyr Ser Asp Ser Phe Lys lie Lys His Leu Gly Lys Gly His 20 25 30 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.4" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: Leu Gin Lys Glu Leu Lys Arg lie Lys lie Pro Asp Tyr Ser Asp Ser 1 5 10 15 Phe Lys lie Lys His Leu 20 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.l" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: Gin Gin Gly Thr Ala Ala Leu Gin Lys Glu Leu Lys Arg lie Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.54" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: Gly Thr Ala Ala Leu Gin Lys Glu Leu Lys Arg lie Lys lie Pro 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 35 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "Domain II" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: Ser Ser Gin lie Ser Met Val Pro Asn Val Gly Leu Lys Phe Ser lie 1 5 10 15 Ser Asn Ala Asn lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg 20 25 30 Phe Leu Lys 35 (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.2" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.8' (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 16 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc__feature (D) OTHER INFORMATION: "BPI.58" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: Cys lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu 1 5 10 15 Lys (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.65 oxidized" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: Cys lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu 1 5 10 15 Lys Cys (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 27 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.3" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:ll: Asn Val Gly Leu Lys Phe Ser lie Ser Asn Ala Asn lie Lys lie Ser 1 5 10 15 Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys 20 25 (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 28 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "Domain III" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: Val His Val His lie Ser Lys Ser Lys Val Gly Trp Leu lie Gin Leu 1 5 10 15 Phe His Lys Lys lie Glu Ser Ala Leu Arg Asn Lys 20 25 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.11" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: Lys Ser Lys Val Trp Leu lie Gin Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (i ) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.12" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: Ser Val His Val His lie Ser Lys Ser Lys Val Gly Trp Leu lie Gin 1 5 10 15 Leu Phe His Lys Lys lie Glu Ser Ala Leu Arg Asn Lys 20 25 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.13" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: Lys Ser Lys Val Gly Trp Leu lie Gin Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.15" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: Ala Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.16" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: lie Ala lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.17" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: lie Lys Ala Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.18" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: lie Lys lie Ala Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.19" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: lie Lys lie Ser Ala Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.20" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: lie Lys lie Ser Gly Ala Trp Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: 1inear (ii) MOLECULE TYPE: peptide (i ) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.21" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: lie Lys lie Ser Gly Lys Ala Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.22" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: lie Lys lie Ser Gly Lys Trp Ala Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.23" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: lie Lys lie Ser Gly Lys Trp Lys Ala Ala Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (i ) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.24" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: lie Lys lie Ser Gly Lys Trp Lys Ala Gin Ala Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.25" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Ala Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:27: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.26" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Ala Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.27" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe Ala Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:29: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.28" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu Ala 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:30: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.59" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30: lie Lys lie Ser Gly Ala Trp Ala Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:31: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.45" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: lie Lys lie Ser Gly Lys Trp Lys Ala Ala Ala Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:32: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.60" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: lie Ala lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu Ala 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:33: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.31" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: Ala Ser Lys Val Gly Trp Leu lie Gin Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:34: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide . (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.32" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: Lys Ala Lys Val Gly Trp Leu lie Gin Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:35: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.33" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35: Lys Ser Ala Val Gly Trp Leu lie Gin Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:36: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.34" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36: Lys Ser Lys Ala Gly Trp Leu lie Gin Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:37: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.35" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: Lys Ser Lys Val Ala Trp Leu lie Gin Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:38: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.36" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38: Lys Ser Lys Val Gly Ala Leu lie Gin Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:39: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.37" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39: Lys Ser Lys Val Gly Trp Ala lie Gin Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:40: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.38" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40: Lys Ser Lys Val Gly Trp Leu Ala Gin Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:41: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.39" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: Lys Ser Lys Val Gly Trp Leu lie Ala Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:42: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.40" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42: Lys Ser Lys Val Gly Trp Leu lie Gin Ala Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:43: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "EPI.41" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43: Lys Ser Lys Val Gly Trp Leu lie Gin Leu Ala His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:44: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: 1inear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.42" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44: Lys Ser Lys Val Gly Trp Leu lie Gin Leu Phe Ala Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:45: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.43" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45: Lys Ser Lys Val Gly Trp Leu lie Gin Leu Phe His Ala Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.44" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46: Lys Ser Lys Val Gly Trp Leu lie Gin Leu Phe His Lys Ala 1 5 10 [2) INFORMATION FOR SEQ ID NO:47: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.56" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47: lie Lys lie Ser Gly Lys Trp Lys Ala Lys Gin Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:48: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.61" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48: lie Lys lie Ser Gly Lys Phe Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:49: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.66" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 5..7 (D) OTHER INFORMATION: /label= D-Trp /note= "The amino acid at position 7 is D-tryptophan" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49: lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu Ly. 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:50: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.67" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 6..8 (D) OTHER INFORMATION: /label= Substituted-Ala /note= "The alanine at position 7 is beta-1-naphthyl-substituted" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50: lie Lys lie Ser Gly Lys Ala Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:51: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.9" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51: Lys Arg Phe Leu Lys Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:52: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.30" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52: Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys Lys Ser Lys Val Gly Trp 1 5 10 15 Leu lie Gin Leu Phe His Lys Lys 20 (2) INFORMATION FOR SEQ ID NO:53: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.63" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53: lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys Lys 1 5 10 15 Ser Lys Val Gly Trp Leu lie Gin Leu Phe His Lys Lys 20 25 (2) INFORMATION FOR SEQ ID NO:54: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.7" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54: Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys Lys Trp Lys Ala Gin Lys 1 5 10 15 Arg Phe Leu Lys 20 (2) INFORMATION FOR SEQ ID NO:55: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.10.1" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55: Lys Arg Phe Leu Lys Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys Lys 1 5 10 15 Trp Lys Ala Gin Lys Arg Phe Leu Lys 20 25 (2) INFORMATION FOR SEQ ID NO:56: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 28 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.29" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56: Lys Ser Lys Val Gly Trp Leu lie Gin Leu Phe His Lys Lys Lys Ser 1 5 10 15 Lys Val Gly Trp Leu lie Gin Leu Phe His Lys Lys 20 25 (2) INFORMATION FOR SEQ ID NO:57: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.46' (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57: Lys Trp Lys Ala Ala Ala Arg Phe Leu Lys Lys Trp Lys Ala Gin Lys 1 5 10 15 Arg Phe Leu Lys 20 (2) INFORMATION FOR SEQ ID NO:58: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (i ) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.47" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58: Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys Lys Trp Lys Ala Ala Ala 1 5 10 15 Arg Phe Leu Lys 20 (2) INFORMATION FOR SEQ ID NO:59: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.48" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59: Lys Trp Lys Ala Ala Ala Arg Phe Leu Lys Lys Trp Lys Ala Ala Ala 1 5 10 15 Arg Phe Leu Lys 20 (2) INFORMATION FOR SEQ ID NO:60: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 30 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.69" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60: Lys Trp Lys Ala Ala Ala Arg Phe Leu Lys Lys Trp Lys Ala Ala Ala 1 5 10 15 Arg Phe Leu Lys Lys Trp Lys Ala Ala Ala Arg Phe Leu Lys 20 25 30 (2) INFORMATION FOR SEQ ID NO:61: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 21 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.55" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61: Gly Trp Leu lie Gin Leu Phe His Lys Lys lie Glu Ser Ala Leu Arg 1 5 10 15 Asn Lys Met Asn Ser 20 (2) INFORMATION FOR SEQ ID NO:62: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: 1inear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.73" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62: lie Lys lie Ser Gly Lys Trp Lys Ala Gin Phe Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:63: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.70" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 8..10 (D) OTHER INFORMATION: /label= Substituted-Ala /note= "The alanine at position 7 is be a-3-pyridyl-substituted" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63: lie Lys lie Ser Gly Lys Ala Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:64: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.71" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 13..15 (D) OTHER INFORMATION: /label= Substituted-Ala /note= "The alanine at position 13 is beta-3-pyridyl-substituted" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66: lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Ala Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:65: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.10.2" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65: Gin Lys Arg Phe Leu Lys Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys 20 25 (2) INFORMATION FOR SEQ ID NO:66: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.72" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 1..3 (D) OTHER INFORMATION: /label= D-alanine /note= "The position 1 and position 2 alanine residues are both D-alanine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64: Ala Ala lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu 1 5 10 15 Lys (2) INFORMATION FOR SEQ ID NO:67: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.5" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67: Val His Val His lie Ser Lys Ser Lys Val Gly Trp Leu lie Gin Leu 1 5 10 15 Phe His Lys Lys lie Glu 20 (2) INFORMATION FOR SEQ ID NO:68: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (i ) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.65 reduced" (ix) FEATURE: (A) NAME/KEY: Disulfide-bond (B) LOCATION: 1..17 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68: Cys lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe Leu Lys 1 5 10 15 Cys (2) INFORMATION FOR SEQ ID NO:69: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 487 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (i ) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "rBPI" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69: Met Arg Glu Asn Met Ala Arg Gly Pro Cys Asn Ala Pro Arg Trp Val -31 -30 -25 -20 Ser Leu Met Val Leu Val Ala lie Gly Thr Ala Val Thr Ala Ala Val -15 -10 -5 1 Asn Pro Gly Val Val Val Arg lie Ser Gin Lys Gly Leu Asp Tyr Ala 5 10 15 Ser Gin Gin Gly Thr Ala Ala Leu Gin Lys Glu Leu Lys Arg lie Lys 20 25 30 lie Pro Asp Tyr Ser Asp Ser Phe Lys lie Lys His Leu Gly Lys Gly 35 40 45 His Tyr Ser Phe Tyr Ser Met Asp lie Arg Glu Phe Gin Leu Pro Ser 50 55 60 65 Ser Gin lie Ser Met Val Pro Asn Val Gly Leu Lys Phe Ser lie Ser 70 75 80 Asn Ala Asn lie Lys lie Ser Gly Lys Trp Lys Ala Gin Lys Arg Phe 85 90 95 Leu Lys Met Ser Gly Asn Phe Asp Leu Ser lie Glu Gly Met Ser lie 100 105 110 Ser Ala Asp Leu Lys Leu Gly Ser Asn Pro Thr Ser Gly Lys Pro Thr 115 120 125 lie Thr Cys Ser Ser Cys Ser Ser His lie Asn Ser Val His Val His 130 135 140 145 lie Ser Lys Ser Lys Val Gly Trp Leu He Gin Leu Phe His Lys Lys 150 155 160 He Glu Ser Ala Leu Arg Asn Lys Met Asn Ser Gin Val Cys Glu Lys 165 170 175 Val Thr Aαn Ser Val Ser Ser Lys Leu Gin Pro Tyr Phe Gin Thr Leu 180 185 190 Pro Val Met Thr Lys He Asp Ser Val Ala Gly He Asn Tyr Gly Leu 195 200 205 Val Ala Pro Pro Ala Thr Thr Ala Glu Thr Leu Asp Val Gin Met Lys 210 215 220 225 Gly Glu Phe Tyr Ser Glu Asn His His Asn Pro Pro Pro Phe Ala Pro 230 235 240 Pro Val Met Glu Phe Pro Ala Ala His Asp Arg Met Val Tyr Leu Gly 245 250 255 Leu Ser Asp Tyr Phe Phe Asn Thr Ala Gly Leu Val Tyr Gin Glu Ala 260 265 270 Gly Val Leu Lys Met Thr Leu Arg Asp Asp Met He Pro Lys Glu Ser 275 280 285 Lys Phe Arg Leu Thr Thr Lys Phe Phe Gly Thr Phe Leu Pro Glu Val 290 295 300 305 Ala Lys Lys Phe Pro Asn Met Lys He Gin He His Val Ser Ala Ser 310 315 320 Thr Pro Pro His Leu Ser Val Gin Pro Thr Gly Leu Thr Phe Tyr Pro 325 330 335 Ala Val Asp Val Gin Ala Phe Ala Val Leu Pro Asn Ser Ser Leu Ala 340 345 350 Ser Leu Phe Leu He Gly Met His Thr Thr Gly Ser Met Glu Val Ser . 355 360 365 Ala Glu Ser Asn Arg Leu Val Gly Glu Leu Lys Leu Asp Arg Leu Leu 370 375 380 385 Leu Glu Leu Lys His Ser Asn He Gly Pro Phe Pro Val Glu Leu Leu 390 395 400 Gin Asp He Met Asn Tyr He Val Pro He Leu Val Leu Pro Arg Val 405 410 415 Asn Glu Lys Leu Gin Lys Gly Phe Pro Leu Pro Thr Pro Ala Arg Val 420 425 430 Gin Leu Tyr Asn Val Val Leu Gin Pro His Gin Asn Phe Leu Leu Phe 435 440 445 Gly Ala Asp Val Val Tyr Lys 450 455 (2) INFORMATION FOR SEQ ID NO:70: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.74" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70: Lys Ser Lys Val Gly Trp Leu He Gin Leu Phe His Lys Lys Lys 1 5 10 15 Trp Lys Ala Gin Lys Arg Phe Leu Lys 20 (2) INFORMATION FOR SEQ ID NO:71: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.76" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 10..12 (D) OTHER INFORMATION: /label= D-Phe /note= "The amino acid at position 11 is D-phenylalanine" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71: He Lys He Ser Gly Lys Trp Lys Ala Gin Phe Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:72: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.77" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72: He Lys He Ser Gly Lys Trp Lys Ala Gin Trp Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:73: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide ( ix ) FEATURE : (A ) NAME/KEY : misc_f eature ( D ) OTHER INFORMATION : "BPI . 79 " ( xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 73 : He Lys He Ser Gly Lys Trp Lys Ala Lys Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:74: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.80" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 10..12 (D) OTHER INFORMATION: /label= Substituted-Ala /note= "The alanine at position 11 is beta-1-naphthyl-substituted" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74: He Lys He Ser Gly Lys Trp Lys Ala Gin Ala Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:75: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.81" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75: He Lys He Ser Gly Lys Trp Lys Ala Phe Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:76: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.82" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76: Lys Ser Lys Val Gly Trp Leu He Gin Leu Trp His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:77: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.83" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 10..12 (D) OTHER INFORMATION: /label= Substituted-Ala /note= "The alanine at position 6 is beta-1-naphthyl-substituted" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77: Lys Ser Lys Val Gly Ala Lys He Gin Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:78: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.84" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 6..8 (D) OTHER INFORMATION: /label= Substituted-Ala /note= "The alanine at position 7 is be a-1-naphthyl-substituted" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78: He Lys He Ser Gly Lys Ala Lys Ala Gin Phe Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:79: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.85" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:79: Lys Ser Lys Val Leu Trp Leu He Gin Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:80: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.86" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80: Lys Ser Lys Val Gly Trp Leu He Leu Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:81: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.87" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81: Lys Ser Lys Val Gly Trp Leu He Gin Leu Phe Leu Lys Lys 10 (2) INFORMATION FOR SEQ ID NO:82: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.88" (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:82: He Lys He Ser Gly Lys Trp Lys Ala Phe Phe Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:83: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.98" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 6..8 (D) OTHER INFORMATION: /label= Substituted-Ala /note= "The alanine at position 7 is be a-1-naphthyl-substituted" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83: He Lys He Ser Gly Lys Ala Lys Ala Gin Phe Arg Phe Leu Lys 1 5 10 15 Lys Ser Lys Val Gly Trp Leu He Phe Leu Phe His Lys Lys 20 25 (2) INFORMATION FOR SEQ ID NO:84: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.89" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 6..8 (D) OTHER INFORMATION: /label= Substituted-Ala /note= "The alanine at position 7 is beta-1-naphthyl-substituted" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84: He Lys He Ser Gly Lys Ala Lys Ala Phe Lys Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:85: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.90" (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 6..8 (D ) OTHER INFORMATION: /label= Substituted-Ala /note= "The alanine at position 7 is be a-1-naphthyl-substituted" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 85 : He Lys He Ser Gly Lys Ala Lys Ala Phe Phe Arg Phe Leu Lys 1 5 10 15 (2) INFORMATION FOR SEQ ID NO:86: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.91" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86: Lys Ser Lys Val Gly Trp Leu He Phe Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:87: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.92" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87: Lys Ser Lys Val Gly Trp Leu He Lys Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:88: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: miεc_feature (D) OTHER INFORMATION: "BPI.93' (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 6..8 (D) OTHER INFORMATION: /label= Substituted-Ala /note= "The alanine at position 7 is bet -1-naphthyl-substituted" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88: He Lys He Ser Gly Lys Ala Lys Ala Gin Phe Arg Phe Leu Lys 1 5 10 15 Lys Ser Lys Val Gly Trp Leu He Gin Leu Phe His Lys Lys 20 25 (2) INFORMATION FOR SEQ ID NO:89: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (i ) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.94" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89: Lys Ser Lys Val Gly Trp Leu He Gin Leu Phe Phe Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:90: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.95" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90: Lys Ser Lys Val Phe Trp Leu He Gin Leu Phe His Lys Lys 10 (2) INFORMATION FOR SEQ ID NO:91: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.96" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:91: Lys Ser Lys Val Gly Trp Leu He Gin Leu Phe His Lys Phe 1 5 10 (2) INFORMATION FOR SEQ ID NO:92: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.97" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92: Lys Ser Lys Val Lys Trp Leu He Gin Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO: 3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 30 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.99" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93: Lys Trp Lys Ala Gin Trp Arg Phe Leu Lys Lys Trp Lys Ala Gin 1 5 10 15 Trp Arg Phe Leu Lys Lys Trp Lys Ala Gin Trp Arg Phe Leu Lys 20 25 30 (2) INFORMATION FOR SEQ ID NO:94: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.100" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94: Lys Ser Lys Val Lys Trp Leu He Lys Leu Phe His Lys Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO:95: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 28 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.101" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:95: Lys Ser Lys Val Lys Trp Leu He Lys Leu Phe Phe Lys Phe Lys Ser 1 5 10 15 Lys Val Lys Trp Leu He Lys Leu Phe Phe Lys Phe 20 25 (2) INFORMATION FOR SEQ ID NO:96: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "BPI.102" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96: Lys Trp Lys Ala Gin Phe Arg Phe Leu Lys Lys Ser Lys Val Gly Trp 1 5 10 15 Leu He Leu Leu Phe His Lys Lys 20 [2) INFORMATION FOR SEQ ID NO:97: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1443 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1443 (ix) FEATURE: (A) NAME/KEY: mat_peptide (B) LOCATION: 76..1443 (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "rLBP" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:97: ATG GGG GCC TTG GCC AGA GCC CTG CCG TCC ATA CTG CTG GCA TTG CTG 48 Met Gly Ala Leu Ala Arg Ala Leu Pro Ser He Leu Leu Ala Leu Leu -25 -20 -15 -10 CTT ACG TCC ACC CCA GAG GCT CTG GGT GCC AAC CCC GGC TTG GTC GCC 96 Leu Thr Ser Thr Pro Glu Ala Leu Gly Ala Asn Pro Gly Leu Val Ala -5 1 5 AGG ATC ACC GAC AAG GGA CTG CAG TAT GCG GCC CAG GAG GGG CTA TTG 144 Arg He Thr Asp Lys Gly Leu Gin Tyr Ala Ala Gin Glu Gly Leu Leu 10 15 20 GCT CTG CAG AGT GAG CTG CTC AGG ATC ACG CTG CCT GAC TTC ACC GGG 192 Ala Leu Gin Ser Glu Leu Leu Arg He Thr Leu Pro Asp Phe Thr Gly 25 30 35 GAC TTG AGG ATC CCC CAC GTC GGC CGT GGG CGC TAT GAG TTC CAC AGC 240 Asp Leu Arg He Pro His Val Gly Arg Gly Arg Tyr Glu Phe His Ser 40 45 50 55 CTG AAC ATC CAC AGC TGT GAG CTG CTT CAC TCT GCG CTG AGG CCT GTC 288 Leu Asn He His Ser Cys Glu Leu Leu His Ser Ala Leu Arg Pro Val 60 65 70 CCT GGC CAG GGC CTG AGT CTC AGC ATC TCC GAC TCC TCC ATC CGG GTC 336 Pro Gly Gin Gly Leu Ser Leu Ser He Ser Asp Ser Ser He Arg Val 75 80 85 CAG GGC AGG TGG AAG GTG CGC AAG TCA TTC TTC AAA CTA CAG GGC TCC 384 Gin Gly Arg Trp Lys Val Arg Lys Ser Phe Phe Lys Leu Gin Gly Ser 90 95 100 TTT GAT GTC AGT GTC AAG GGC ATC AGC ATT TCG GTC AAC CTC CTG TTG 432 Phe Asp Val Ser Val Lys Gly He Ser He Ser Val Asn Leu Leu Leu 105 110 115 GGC AGC GAG TCC TCC GGG AGG CCC ACA GTT ACT GCC TCC AGC TGC AGC 480 Gly Ser Glu Ser Ser Gly Arg Pro Thr Val Thr Ala Ser Ser Cys Ser 120 125 130 135 AGT GAC ATC GCT GAC GTG GAG GTG GAC ATG TCG GGA GAC TTG GGG TGG 528 Ser Asp He Ala Asp Val Glu Val Asp Met Ser Gly Asp Leu Gly Trp 140 145 150 CTG TTG AAC CTC TTC CAC AAC CAG ATT GAG TCC AAG TTC CAG AAA GTA 576 Leu Leu Asn Leu Phe His Asn Gin He Glu Ser Lys Phe Gin Lys Val 155 160 165 CTG GAG AGC AGG ATT TGC GAA ATG ATC CAG AAA TCG GTG TCC TCC GAT 624 Leu Glu Ser Arg He Cys Glu Met He Gin Lys Ser Val Ser Ser Asp 170 175 180 CTA CAG CCT TAT CTC CAA ACT CTG CCA GTT ACA ACA GAG ATT GAC AGT 672 Leu Gin Pro Tyr Leu Gin Thr Leu Pro Val Thr Thr Glu He Asp Ser 185 190 195 TTC GCC GAC ATT GAT TAT AGC TTA GTG GAA GCC CCT CGG GCA ACA GCC 720 Phe Ala Asp He Asp Tyr Ser Leu Val Glu Ala Pro Arg Ala Thr Ala 200 205 210 215 CAG ATG CTG GAG GTG ATG TTT AAG GGT GAA ATC TTT CAT CGT AAC CAC 768 Gin Met Leu Glu Val Met Phe Lys Gly Glu He Phe His Arg Asn His 220 225 230 CGT TCT CCA GTT ACC CTC CTT GCT GCA GTC ATG AGC CTT CCT GAG GAA 816 Arg Ser Pro Val Thr Leu Leu Ala Ala Val Met Ser Leu Pro Glu Glu 235 240 245 CAC AAC AAA ATG GTC TAC TTT GCC ATC TCG GAT TAT GTC TTC AAC ACG 864 His Asn Lys Met Val Tyr Phe Ala He Ser Asp Tyr Val Phe Asn Thr 250 255 260 GCC AGC CTG GTT TAT CAT GAG GAA GGA TAT CTG AAC TTC TCC ATC ACA 912 Ala Ser Leu Val Tyr His Glu Glu Gly Tyr Leu Asn Phe Ser He Thr 265 270 275 GAT GAG ATG ATA CCG CCT GAC TCT AAT ATC CGA CTG ACC ACC AAG TCC 960 Asp Glu Met He Pro Pro Asp Ser Asn He Arg Leu Thr Thr Lys Ser 280 285 290 295 TTC CGA CCC TTC GTC CCA CGG TTA GCC AGG CTC TAC CCC AAC ATG AAC 1008 Phe Arg Pro Phe Val Pro Arg Leu Ala Arg Leu Tyr Pro Asn Met Asn 300 305 310 CTG GAA CTC CAG GGA TCA GTG CCC TCT GCT CCG CTC CTG AAC TTC AGC 1056 Leu Glu Leu Gin Gly Ser Val Pro Ser Ala Pro Leu Leu Asn Phe Ser 315 320 325 CCT GGG AAT CTG TCT GTG GAC CCC TAT ATG GAG ATA GAT GCC TTT GTG 1104 Pro Gly Asn Leu Ser Val Asp Pro Tyr Met Glu He Asp Ala Phe Val 330 335 340 CTC CTG CCC AGC TCC AGC AAG GAG CCT GTC TTC CGG CTC AGT GTG GCC 1152 Leu Leu Pro Ser Ser Ser Lys Glu Pro Val Phe Arg Leu Ser Val Ala 345 350 355 ACT AAT GTG TCC GCC ACC TTG ACC TTC AAT ACC AGC AAG ATC ACT GGG 1200 Thr Asn Val Ser Ala Thr Leu Thr Phe Asn Thr Ser Lys He Thr Gly 360 365 370 375 TTC CTG AAG CCA GGA AAG GTA AAA GTG GAA CTG AAA GAA TCC AAA GTT 1248 Phe Leu Lys Pro Gly Lys Val Lys Val Glu Leu Lys Glu Ser Lys Val 380 385 390 GGA CTA TTC AAT GCA GAG CTG TTG GAA GCG CTC CTC AAC TAT TAC ATC 1296 Gly Leu Phe Asn Ala Glu Leu Leu Glu Ala Leu Leu Asn Tyr Tyr He 395 400 405 CTT AAC ACC TTC TAC CCC AAG TTC AAT GAT AAG TTG GCC GAA GGC TTC 1344 Leu Asn Thr Phe Tyr Pro Lys Phe Asn Asp Lys Leu Ala Glu Gly Phe 410 415 420 CCC CTT CCT CTG CTG AAG CGT GTT CAG CTC TAC GAC CTT GGG CTG CAG 1392 Pro Leu Pro Leu Leu Lys Arg Val Gin Leu Tyr Asp Leu Gly Leu Gin 425 430 435 ATC CAT AAG GAC TTC CTG TTC TTG GGT GCC AAT GTC CAA TAC ATG AGA 1440 He His Lys Asp Phe Leu Phe Leu Gly Ala Asn Val Gin Tyr Met Arg 440 445 450 455 GTT 1443 Val (2) INFORMATION FOR SEQ ID NO:98: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 481 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (ix) FEATURE: (A) NAME/KEY: misc_feature (D) OTHER INFORMATION: "rLBP" (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98: Met Gly Ala Leu Ala Arg Ala Leu Pro Ser He Leu Leu Ala Leu Leu -25 -20 -15 -10 Leu Thr Ser Thr Pro Glu Ala Leu Gly Ala Asn Pro Gly Leu Val Ala -5 1 5 Arg He Thr Asp Lys Gly Leu Gin Tyr Ala Ala Gin Glu Gly Leu Leu 10 15 20 Ala Leu Gin Ser Glu Leu Leu Arg He Thr Leu Pro Asp Phe Thr Gly 25 30 35 Asp Leu Arg He Pro His Val Gly Arg Gly Arg Tyr Glu Phe His Ser 40 45 50 55 Leu Asn He His Ser Cys Glu Leu Leu His Ser Ala Leu Arg Pro Val 60 65 70 Pro Gly Gin Gly Leu Ser Leu Ser He Ser Asp Ser Ser He Arg Val 75 80 85 Gin Gly Arg Trp Lys Val Arg Lys Ser Phe Phe Lys Leu Gin Gly Ser 90 95 100 Phe Asp Val Ser Val Lys Gly He Ser He Ser Val Asn Leu Leu Leu 105 110 115 Gly Ser G.lu Ser Ser Gly Arg Pro Thr Val Thr Ala Ser Ser Cys Ser 120 125 130 135 Ser Asp He Ala Asp Val Glu Val Asp Met Ser Gly Asp Leu Gly Trp 140 145 150 Leu Leu Asn Leu Phe His Asn Gin He Glu Ser Lys Phe Gin Lys Val 155 160 165 Leu Glu Ser Arg He Cys Glu Met He Gin Lys Ser Val Ser Ser Asp 170 175 180 Leu Gin Pro Tyr Leu Gin Thr Leu Pro Val Thr Thr Glu He Asp Ser 185 190 195 Phe Ala Asp He Asp Tyr Ser Leu Val Glu Ala Pro Arg Ala Thr Ala 200 205 210 215 Gin Met Leu Glu Val Met Phe Lys Gly Glu He Phe His Arg Asn His 220 225 230 Arg Ser Pro Val Thr Leu Leu Ala Ala Val Met Ser Leu Pro Glu Glu 235 240 245 His Asn Lys Met Val Tyr Phe Ala He Ser Asp Tyr Val Phe Asn Thr 250 255 260 Ala Ser Leu Val Tyr His Glu Glu Gly Tyr Leu Asn Phe Ser He Thr 265 270 275 Asp Glu Met He Pro Pro Asp Ser Asn He Arg Leu Thr Thr Lys Ser 280 285 290 295 Phe Arg Pro Phe Val Pro Arg Leu Ala Arg Leu Tyr Pro Asn Met Asn 300 305 310 Leu Glu Leu Gin Gly Ser Val Pro Ser Ala Pro Leu Leu Asn Phe Ser 315 320 325 Pro Gly Asn Leu Ser Val Asp Pro Tyr Met Glu He Asp Ala Phe Val 330 335 340 Leu Leu Pro Ser Ser Ser Lys Glu Pro Val Phe Arg Leu Ser Val Ala 345 350 355 Thr Asn Val Ser Ala Thr Leu Thr Phe Asn Thr Ser Lys He Thr Gly 360 365 370 375 Phe Leu Lys Pro Gly Lys Val Lys Val Glu Leu Lys Glu Ser Lys Val 380 385 390 Gly Leu Phe Asn Ala Glu Leu Leu Glu Ala Leu Leu Asn Tyr Tyr He 395 400 405 Leu Asn Thr Phe Tyr Pro Lys Phe Asn Asp Lys Leu Ala Glu Gly Phe 410 415 420 Pro Leu Pro Leu Leu Lys Arg Val Gin Leu Tyr Asp Leu Gly Leu Gin 425 430 435 He His Lys Asp Phe Leu Phe Leu Gly Ala Asn Val Gin Tyr Met Arg 440 445 450 455 Val

Claims: What is claimed is: 1. A peptide which is an amino acid sequence of human bactericidal permeability increasing protein (BPI) from about position 17 to about position 45, subsequences thereof and variants of the sequence or subsequence thereof, having a biological activity that is an activity of BPI. 2. The peptide of claim 1 having the amino acid sequence ASQQGTAALQKELKRIKIPDYSDSFKIKH (SEQ ID NO: 1) GTAALQKELKRIKIPDYSDSFKIKHLGKGH (SEQ ID NO: 2) LQKELKRIKIPDYSDSFKIKHL (SEQ ID NO: 3) QQGTAALQKELKRIK (SEQ ID NO: 4) or GTAALQKELKRIKIP (SEQ ID NO: 5). 3. A peptide which contains two or three of the same or different peptides according to claim 1 covalently linked together. 4. A pharmaceutical composition comprising a peptide according to claim 1 , 2 or 3 and a pharmaceutically-acceptable carrier or diluent. 5. A peptide which is an amino acid sequence of human bactericidal permeability increasing protein (BPI) from about position 65 to about position 99, subsequences thereof and variants of the sequence or subsequence thereof, having a biological activity that is an activity of BPI. 6. The peptide of claim 5 having the amino acid sequence SSQISMVPNVGLKFSISNANIKISGKWKAQKRFLK (SEQ ID NO: 6) IKISGKWKAQKRFLK (SEQ ID NO: 7) KWKAQKRFLK (SEQ ID NO: 8) CIKISGKWKAQKRFLK (SEQ ID NO: 9) CIKISGKWKAQKRFLKC (SEQ ID NO: 10) ; NVGLKFSISNANIKISGKWKAQKRFLK (SEQ ID NO: 11) ; AKISGKWKAQKRFLK (SEQ ID NO: 16); IAISGKWKAQKRFLK (SEQID NO: 17 IKASGKWKAQKRFLK (SEQID NO: 18 IKIAGKWKAQKRFLK (SEQID NO: 19 IKISAKWKAQKRFLK (SEQID NO:20 IKISGAWKAQKRFLK (SEQID NO:21 IKISGKAKAQKRFLK (SEQID NO:22 IKISGKWAAQKRFLK (SEQID NO:23 IKISGKWKAAKRFLK (SEQID NO:24 IKISGKWKAQARFLK (SEQID NO:25 IKISGKWKAQKAFLK (SEQID NO:26 IKISGKWKAQKRALK (SEQID NO:27 IKISGKWKAQKRFAK (SEQID NO:28 IKISGKWKAQKRFLA (SEQID NO:29 IKISGAWAAQKRFLK (SEQID NO: 30 IKISGKWKAAARFLK (SEQID NO:31 IAISGKWKAQKRFLA (SEQID NO: 32 IKISGKWKAKQRFLK (SEQID NO:47 IKISGKWKAQWRFLK (SEQID NO:72 IKISGKWKAKKRFLK (SEQID NO:73 IKISGKWKAFKRFLK (SEQID NO:75 IKISGKFKAQKRFLK (SEQID NO:48 IKISGKW D KAQKRFLK (SEQID NO:49 IKISGKWKAFFRFLK (SEQID NO: 82 IKISGKWKAQFRFLK (SEQID NO: 62 IKISGKA^ (3 . pyridyI) KAQKRFLK (SEQID NO:63 IKISGKWKAQKRA /3 . (3 . pyridyI) LK (SEQID NO: 64 A D A D IKISGKWKAQKRFLK (SEQID NO: 66 IKISGKWKAQF D RFLK (SEQID NO:71 IKISGKWKAQA^ a . Mphthyl) RFLK (SEQID NO:74 IKISGKAø.^^KAQFRFLK (SEQID NO:78 ' IKISGKAø. a . ωphΛyI) KAFKRFLK (SEQID NO: 84 IKISGKA^. a . ωphthyI) KAFFRFLK (SEQID NO: 85 or IKISGKA . a . ωphthyI) KAQKRFLK (SEQ ID NO:50). 7. A peptide which contains two or three of the same or different peptides according to claim 5 covalently linked together. 8. The peptide of claim 7 having the amino acid sequence KRFLKKWKAQKRFLK (SEQ ID NO:51) KWKAQKRFLKKWKAQKRFLK (SEQ ID NO:54) KRFLKKWKAQKRFLKKWKAQKRFLK (SEQ ID NO:55) KWKAAARFLKKWKAQKRFLK (SEQ ID NO:57) KWKAQKRFLKKWKAAARFLK (SEQ ID NO:58) KWKAAARFLKKWKAAARFLK (SEQ ID NO:59) KWKAQWRFLKKWKAQWRFLKKWKAQWRFLK (SEQ ID NO:93) KWKAAARFLKKWKAAARFLKKWKAAAPFLK (SEQ ID NO: 60) or QKRFLKKWKAQKRFLKKWKAQKRFLK (SEQ ID NO:65). 9. A pharmaceutical composition comprising a peptide according to claim 5, 6, 7 or 8 and a pharmaceutically-acceptable carrier or diluent. 10. A peptide which is an amino acid sequence of human bactericidal permeability increasing protein (BPI) from about position 142 to about position 169, subsequences thereof and variants of the sequence or subsequence thereof, having a biological activity that is an activity of BPI. 11. The peptide of claim 10 having the amino acid sequence VHVHISKSKVGWLIQLFHKKIES ALRNK (SEQ ID NO: 12 KSKVWLIQLFHKK (SEQ ID NO: 13 VHVfflSKSKVGWLIQLFHKKIE (SEQ ID NO: 67 SVHVHISKSKVGWLIQLFHKKIESALRNK (SEQ ID NO: 14 KSKVGWLIQLFHKK (SEQ ID NO: 15 ASKVGWLIQLFHKK (SEQ ID NO:33 KAKVGWLIQLFHKK (SEQ ID NO: 34 KSAVGWLIQLFHKK (SEQ ID NO: 35 KSKAGWLIQLFHKK (SEQ ID NO: 36 KSKVAWLIQLFHKK (SEQ ID NO: 37 KSKVGALIQLFHKK (SEQ ID NO:38 KSKVGWAIQLFHKK (SEQ ID NO: 39 KSKVGWLAQLFHKK (SEQ ID NO:40 KSKVGWLIALFHKK (SEQ ID NO:41 KSKVGWLIQAFHKK (SEQ ID NO:42 KSKVGWLIQLAHKK (SEQ ID NO:43 KSKVGWLIQLFAKK (SEQ ID NO:44 KSKVGWLIQLFHAK (SEQ ID NO:45 GWLIQLFHKKIESALRNKMNS (SEQ ID NO: 61 KSKVGWLIQLWHKK (SEQ ID NO:76 KSKVLWLIQLFHKK (SEQ ID NO:79 KSKVGWLILLFHKK (SEQ ID NO: 80 KSKVGWLIQLFLKK (SEQ ID NO:81) KSKVGWLIFLFHKK (SEQ ID NO: 86) KSKVGWLIKLFHKK (SEQ ID NO: 87) KSKVGWLIQLFFKK (SEQ ID NO: 89) KSKVFWLIQLFHKK (SEQ ID NO:90) KSKVGWLIQLFHKF (SEQ ID NO:91) KSKVKWLIQLFHKK (SEQ ID NO:92) KSKVKWLIKLFHKK (SEQ ID NO:94) KSKVGA ^ * - ( ( 1 l.- ω na p p h h t t h h y y l l ) )LIQLFHKK (SEQ ID NO:77) or KSKVGWLIQLFHKA (SEQ ID NO:46). 12. A peptide which contains two or three of the same or different peptides according to claim 10 covalently linked together. 13. The peptide of claim 12 having the amino acid sequence KSKVKWLIKLFFKFKSKVKWLIKLFFKF (SEQ ID NO:95); or KSKVGWLIQLFHKKKSKVGWLIQLFHKK (SEQ ID NO:56). 14. A pharmaceutical composition comprising a peptide according to claim 10, 11, 12 or 13 and a pharmaceutically-acceptable carrier or diluent. 15. A peptide in which two or three of the same or different peptides according to claims 1, 5 or 10 are directly covalently linked together. 16. The peptide of claim 15 having the amino acid sequence KWKAQKRFLKKSKVGWLIQLFHKK (SEQ ID NO:52); IKISGKWKAQKRFLKKSKVGWLIQLFHKK (SEQ ID NO:53); KSKVGWLIQLFHKKKWKAQKRFLK (SEQ ID NO:70); IKISGKAø. (1 . ωphΛyD KAQFRFLKKSKVG iQLFHKK (SEQ ID NO: 88); IKISGKA^ α . ωphthyI) KAQFRFLKKSKVGWLIFLFHKK (SEQ ID NO: 83); or KWKAQFRFLKKSKVGWLILLFHKK (SEQ ID NO:96). 17. A pharmaceutical composition comprising a peptide according to claim 15 or 16 and a pharmaceutically-acceptable carrier or diluent. 18. A method for neutralizing the anti-coagulant effect of heparin comprising administering to a subject an effective amount of a heparin binding peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16. 19. A method of inhibiting angiogenesis comprising administering to a subject an amount of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 product effective to inhibit angiogenesis. 20. The method of claim 19 wherein the angiogenesis inhibited is associated with ocular retinopathy. 21. A method for inhibiting endothelial cell proliferation comprising administering to a subject an amount of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 effective to inhibit proliferation. 22. A method of treating endometriosis comprising administering an amount of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 to the endometrium effective to inhibit endothelial cell proliferation. 23. A method for contraception comprising administering to a subject an amount of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 to the uterine lining effective to prevent endothelial cell proliferation associated with implantation of a fertilized ovum. 24. A method for inhibiting malignant tumor cell proliferation comprising administering to a subject an amount of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 effective to inhibit proliferation. 25. The method of claim 24 wherein the malignant tumor is Kaposi's sarcoma. 26. A method for treating a chronic inflammatory disease state comprising administering to a subject an amount of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 effective to reduce inflammation. 27. The method of claim 26 wherein the chronic inflammatory disease is arthritis. 28. The method of claim 27 wherein the arthritic inflammatory disease state is rheumatoid arthritis. 29. The method of claim 27 wherein the arthritic inflammatory disease state treated is reactive arthritis. 30. A peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for use as a heparin binding medicament. 31. A peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for heparin binding use in neutralizing the anti-coagulant effect of heparin. 32. A peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for heparin binding use in inhibiting angiogenesis. 33. A peptide according to claim 32 wherein the angiogenesis inhibited is associated with ocular retinopathy. 34. A peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for heparin binding use in inhibiting endothelial cell proliferation. 35. A peptide according to claim 32 wherein the endothelial cell proliferation is associated with endometriosis. 36. A peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for heparin binding use as a contraceptive. 37. A peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for heparin binding use in inhibiting malignant tumor cell proliferation. 38. A peptide according to claim 37 wherein the malignant tumor is Kaposi's sarcoma. 39. A peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for heparin binding use in treating a chronic inflammatory disease state. 40. A peptide according to claim 39 wherein the chronic inflammatory disease is arthritis. 41. A peptide according to claim 40 wherein the arthritic inflammatory disease is rheumatoid arthritis. 42. A peptide according to claim 40 wherein the arthritic inflammatory disease is reactive arthritis. 43. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for the manufacture of a heparin binding medicament. 44. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for the manufacture of a heparin binding medicament for neutralizing the anti¬ coagulant effect of heparin. 45. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for the manufacture of a heparin binding medicament for inhibiting angiogenesis. 46. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for the manufacture of a heparin binding medicament for inhibiting angiogenesis associated with ocular retinopathy. 47. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for the manufacture of a heparin binding medicament for inhibiting endothelial cell proliferation. 48. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for the manufacture of a heparin binding medicament for treating endometriosis by inhibiting endothelial cell proliferation. 49. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for the manufacture of a heparin binding contraceptive. 50. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for the manufacture of a heparin binding medicament for inhibiting malignant tumor cell proliferation. 51. The use according to claim 50 wherein the malignant tumor is Kaposi's sarcoma. 52. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for the manufacture of a heparin binding medicament for treatment of a chronic inflammatory disease state. 53. The use according to claim 52 wherein the chronic inflammatory disease is arthritis. 54. The use according to claim 53 wherein the arthritis inflammatory disease is rheumatoid arthritis. 55. The use according to claim 53 wherein the arthritis inflammatory disease is reactive arthritis. 56. A method of treating a Gram-negative bacterial infection and the sequelae thereof in a subject comprising administering a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16. 57. A pharmaceutical composition for treatment of Gram-negative infection and the sequelae thereof in a subject comprising an effective amount of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16. 58. A pharmaceutical composition of claim 57 comprising a pharmaceutically effective diluent, adjuvant, or carrier. 59. Use of a peptide of claim 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 in the manufacture of a medicament for treatment of Gram-negative bacterial infection and the sequelae thereof. 60. A method of treating the adverse effects of Gram-negative endotoxin in blood circulation in a subject comprising administering a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16. 61. A pharmaceutical composition for treatment of the adverse effects of Gram-negative bacterial endotoxin in blood circulation comprising a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16. 62. A pharmaceutical composition of claim 61 comprising a pharmaceutically acceptable diluent, adjuvant or carrier. 63. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11 , 12, 13, 15 or 16 in the manufacture of a medicament for treatment of the adverse effects of Gram-negative endotoxin in blood circulation. 64. A method of killing Gram-negative bacteria comprising administering a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16. 65. A pharmaceutical composition for killing Gram-negative bacteria comprising an effective amount of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16. 66. A pharmaceutical composition of claim 65 comprising a pharmaceutically acceptable diluent, adjuvant or carrier. 67. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 in the manufacture of a medicament for killing Gram-negative bacteria. 68. A method of treating adverse physiological effects associated with depressed reticuloendothelial system function comprising administering to a subject suffering from depressed reticuloendothelial system function an effective amount of a peptide of claim 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16. 69. The method of claim 68 wherein said depressed reticuloendothelial system function comprises diminished function of Kupffer cells of the liver. 70. The method of claim 69 wherein said diminished Kupffer cell function results from physical insult to the liver. 71. The method of claim 69 wherein said diminished Kupffer cell function results from chemical insult to the liver. 72. The method of claim 69 wherein said diminished Kupffer cell function results from biological insult to the liver. 73. The method of claim 68 wherein said peptide is administered in conjunction with a pharmaceutically-acceptable diluent, adjuvant or carrier. 74. A pharmaceutical composition for treatment of the adverse physiological effects associated with depressed reticuloendothelial system function comprising an effective amount of a peptide of claim 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16. 75. A pharmaceutical composition according to claim 74 comprising a pharmaceutically acceptable diluent, adjuvant or carrier. 76. Use of a peptide of claim 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for the manufacture of a medicament for treatment of adverse physiological effects associated with depressed reticuloendothelial cell function. 77. A method of treating a Gram-negative bacterial infection and the sequelae thereof in a subject comprising administering a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 and an antibiotic in synergistically effective amounts. 78. The method of claim 77 wherein the antibiotic is a non-protein antibiotic. 79. The method of claim 77 wherein the antibiotic is selected from the group consisting of gentamicin, polymyxin B and cefamandole nafate. 80. The method of claim 77 wherein said antibiotic and said peptide are administered in amounts where each would alone be bactericidally effective against a Gram-negative bacterial infection. 81. The method of claim 77 wherein said peptide and the antibiotic are administered systemically. 82. The method of claim 77 wherein said peptide and the antibiotic are administered topically. 83. A method of killing Gram-negative bacteria comprising administering a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 and an antibiotic in synergistically effective amounts. 84. The method of claim 83 wherein said peptide and said antibiotic are administered in vivo. 85. The method of claim 84 wherein said peptide and said antibiotic are administered systemically. 86. The method of claim 84 wherein said peptide and said antibiotic are administered topically. 87. The method of claim 83 wherein said peptide and said antibiotic are administered in vitro. 88. The method of claim 83 wherein said antibiotic is selected from the group consisting if gentamicin, polymyxin B and cefamandole nafate. 89. A pharmaceutical composition for treatment of Gram-negative bacterial infection and the sequelae thereof comprising a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 and an antibiotic in synergistically effective amounts. 90. The pharmaceutical composition of claim 89 comprising a pharmaceutically acceptable diluent, adjuvant or carrier. 91. The pharmaceutical composition of claim 89 wherein said antibiotic is selected from the group consisting of gentamicin, polymyxin B and cefamandole nafate. 92. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 and an antibiotic in synergistically effective amounts for the manufacture of a medicament for treatment of Gram-negative bacterial infections and the sequelae thereof. 93. The use of claim 92 wherein said antibiotic is selected from the group consisting of gentamicin, polymyxin B and cefamandole nafate. 94. A method of treating a Gram-negative bacterial infection and the sequelae thereof in a subject comprising administering a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 and an LBP protein product. 95. The method of claim 94 wherein the LBP protein product is administered in an amount effective to potentiate the bactericidal properties of said peptide. 96. The method of claim 94 wherein the LBP protein product is an amino-terminal LBP fragment. 97. The method of claim 94 wherein the LBP protein product is characterized by a molecular weight of about 25 kD. 98. The method of claim 94 wherein the LBP protein product is LBP holoprotein. 99. The method of claim 94 wherein the proteins are administered systemically. 100. The method of claim 94 wherein the proteins are administered topically. 101. A method of killing Gram-negative bacteria comprising administering a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 in combination with an LBP protein product in an amount effective to potentiate the bactericidal properties of said peptide. 102. The method of claim 101 wherein said peptide and said LBP protein product are administered in vivo. 103. The method of claim 101 wherein said peptide and said LBP protein product are administered in vitro. 104. The method of claim 101 wherein the LBP protein product is an amino-terminal LBP fragment. 105. The method of claim 101 wherein the LBP protein product is characterized by a molecular weight of about 25 kD. 106. The method of claim 101 wherein the LBP protein product is holoprotein. 107. A pharmaceutical composition for treatment of Gram-negative bacterial infection and the sequelae thereof comprising a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 and an LBP protein product in an amount effective to potentiate the bactericidal properties of said peptide. 108. The pharmaceutical composition of claim 107 comprising a pharmaceutically acceptable diluent, adjuvant or carrier. 109. The pharmaceutical composition of claim 107 wherein the LBP protein product is an amino-terminal LBP fragment. 110. The pharmaceutical composition of claim 107 wherein the LBP protein product is characterized by a molecular weight of about 25 kD. 111. A Gram-negative cytotoxic composition comprising a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 and an LBP protein product in an amount effective to potentiate the bactericidal properties of said functional domain peptide. 112. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 and an LBP protein product for the manufacture of a medicament for treating a Gram-negative infection and the sequelae thereof. 113. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 and an LBP protein product for the manufacture of a medicament for killing Gram-negative bacteria. 114. A method of treating a subject suffering from infection with Mycobacteria which comprises administering to the subject a composition comprising a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16. 115. The method of claim 114 wherein the composition is administered orally. 116. The method of claim 114 wherein the composition is administered intravenously. 117. The method of claim 114 wherein the composition is administered as an aerosol. 118. The method of claim 114 for the treatment of infection with a Mycobacterium species bacterium selected from the group consisting of M. tuberculosis, M. leprae and M.avium. 119. The method of claim 114 wherein the composition further comprises an antibiotic. 120. The method of claim 114 wherein the composition further comprises a surfactant. 121. A method of treating a subject suffering from the adverse physiological effects of the presence of lipoarabinomannan in circulation, said method comprising administering to the subject a composition comprising apeptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16. 122. The method of claim 121 wherein the adverse physiological effects comprise compromised immune response to microbes or tumor cells due to lipoarabinomannan-induced inhibition of macrophage activation by T-cell lymphokines. 123. The method of claim 121 wherein the adverse physiological effects comprise increased production of a cytokine by the subject. 124. The method of claim 121 wherein the composition is administered orally. 125. The method of claim 121 wherein the composition is administered intravenously. 126. The method of claim 121 wherein the composition is administered as an aerosol. 127. The method of claim 121 wherein the composition further comprises a surfactant. 128. A method for decontaminating a fluid containing lipoarabinomannan, said method comprising contacting the fluid with a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 under conditions such that lipoarabinomannan therein binds said peptide and separating said bound materials from said fluid. 129. The method of claim 128 wherein the fluid is selected from the group consisting of blood, plasma, blood serum, and bone marrow. 130. The method of claim 128 wherein the fluid is selected from the group consisting of an isotonic solution, a pharmaceutical agent, and a cell culture reagent. 131. A pharmaceutical composition for treatment of Mycobacteria infection comprising an effective amount of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16. 132. A pharmaceutical composition of claim 131 comprising a pharmaceutically acceptable diluent adjuvant or carrier. 133. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for the manufacture of a medicament for treatment of Mycobacteria infection. 134. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for the manufacture of a medicament for treatment of the adverse physiological effects of the presence of lipoarabinomannan in circulation. 135. A method for treating a subject suffering from a disease state associated with infection by a species of bacteria from the genus Helicobacter which comprises administering to the subject a composition comprising a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16. 136. The method of claim 135 wherein the site of infection is the gastrointestinal tract. 137. The method of claim 136 wherein the infective bacteria is Helicobacter pylori. 138. The method of claim 137 wherein the disease state is gastritis. 139. The method of claim 137 wherein the disease state is peptic ulcer disease. 140. The method of claim 139 wherein the disease state is gastric ulcer disease. 141. The method of claim 140 wherein the disease state is duodenal ulcer disease. 142. The method of claim 135 wherein the composition is administered intravenously. 143. The method of claim 135 wherein the composition is administered orally. 144. The method of claim 135 wherein the composition further comprises an antibiotic. 145. The method of claim 135 wherein the composition further comprises a surfactant. 146. The method of claim 135 wherein the composition further comprises a bismuth compound. 147. Use of a peptide of claims 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 15 or 16 for the manufacture of a medicament for treatment of a disease state associated with infection by a species of bacteria from the genus Helicobacter. 148. The use according to claim 147 wherein the site of infection is the gastrointestinal tract. 149. The use according to claim 147 wherein the infective bacteria is Helicobacter pylori. 150. The use according to claim 147 wherein the disease state is gastritis. 151. The use according to claim 147 wherein the disease state is peptic ulcer disease. 152. The use according to claim 147 wherein the disease state is gastric ulcer disease. 153. The use according to claim 147 wherein the disease state is duodenal ulcer disease. 154. The use according to claim 147 wherein the medicament is formulated for intravenous administration. 155. The use according to claim 147 wherein the medicament is formulated for oral administration. 156. The use according to claim 147 for the manufacture of a medicament including an antibiotic.

Inventors: LITTLE ROGER G II, LITTLE, ROGER, G., II
Applicants: XOMA CORP, XOMA CORPORATION
Application year: 1994
Main classification: C07K7
IPC codes: A61K9, A61K38, A61P1, A61P3, A61P7, A61P9, A61P13, A61P15, A61P17, A61P19, A61P27, A61P29, A61P31, A61P35, A61P37, A61P43, C07K7, C07K14, C12P21